Compositions and uses of alpha-adrenergic agents

ABSTRACT

The disclosure provides cosmetic and therapeutic compositions of alpha-adrenergic agents. Compositions of the disclosure may be used for topical, transdermal or parenteral administration to the eye or eyelid. The compositions of the disclosure may be used cosmetically to improve the appearance of the eye or therapeutically to treat ptosis.

CROSS-REFERENCE

This application is a Divisional Application of U.S. application Ser.No. 16/043,725, filed Jul. 24, 2018, which is a Continuation Applicationof International Patent Application No. PCT/US2017/015181, filed Jan.26, 2017, which claims the benefit of U.S. Provisional Application No.62/287,391, filed Jan. 26, 2016, each of which is incorporated byreference herein in its entirety.

BACKGROUND OF THE INVENTION

Blepharoplasty is a surgical procedure that involves removal of excessskin, muscle, and fat from the eyelid of a subject. Blepharoplasty maybe prescribed as a treatment for a droopy eyelid, referred to as ptosis,but may also be used to improve the line of vision or change thecosmetic appearance of the eyes of a subject. The procedure was one ofthe top five most commonly performed cosmetic procedures in the UnitedStates with over 200,000 surgeries performed in 2014, according to the2014 Plastic Surgery Report of the American Society of Plastic Surgeons.

Blepharoplasty is an expensive procedure and not accessible to allindividuals who need or want the surgery to repair ptosis or improvetheir eyesight or appearance. The average cost of blepharoplasy in theU.S. in 2014 was approximately $2900 as reported by the American Societyof Plastic Surgeons. While the cost may be covered by health insurancecarriers in particular circumstances, health insurers generally do notcover the cost of cosmetic surgery or its complications.

Non-surgical alternatives to blepharoplasy such as crutch glasses orspecial scleral contact lenses to support the eyelid may be used,however, these alternatives are cumbersome to wear and may not provideadequate relief for subjects. The available surgical alternatives arealso inadequate for individuals seeking cosmetic improvements. Thereforethere remains a need for non-surgical alternatives to blepharoplasty fortherapeutic and cosmetic uses.

SUMMARY OF THE INVENTION

The disclosure provides an eyeshadow composition, comprising adermatologically acceptable carrier, an agent that stimulates Müller'smuscle, and at least one cosmetic excipient. In certain embodiments ofthe eyeshadow composition, the agent that stimulates Müller's musclecomprises an alpha-adrenergic agent. In certain embodiments of theeyeshadow composition, the alpha-adrenergic agent is selected fromnaturally occurring or synthetic alpha-adrenergic agents. In certainembodiments of the eyeshadow composition, the alpha-adrenergic agent isselected from an alpha-1 agonist and an alpha-2 agonist. In certainembodiments of the eyeshadow composition, the alpha-adrenergic agent isselected from amidephrine, anisodamine, anisodine, chloroethylclonidine,cirazoline, desvenlafaxine, dipivefrine, dopamine, ephedrine,epinephrine (adrenaline), etilefrine, ethylnorepinephrine,5-fluronorepinephrine, 6-fluoronorepinephrine, indanidine,levonordefrin, metaraminol, methoxamine, methyldopa, midodrine,naphazoline, norepinephrine (noradrenaline), octopamine, oxymetazoline,phenylephrine, phenylpropanolamine, pseudoephedrine, synephrine,tetrahydrozoline, xylometazoline,6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole,A-61603(N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide),salts of any one thereof, and any combination thereof.

In certain embodiments of the eyeshadow composition, thealpha-adrenergic agent is oxymetazoline or a salt thereof. In certainembodiments of the eyeshadow composition, the alpha-adrenergic agent isoxymetazoline. In certain embodiments of the eyeshadow composition, thealpha-adrenergic agent is not oxymetazoline.

In certain embodiments of the eyeshadow composition, thedermatologically acceptable carrier is selected from a lotion, an oil, acream, a butter, a gel, an ointment, a spray, a milk, and a powder. Incertain embodiments of the eyeshadow composition, the dermatologicallyacceptable carrier is a powder. In certain embodiments of the eyeshadowcomposition, the cosmetic excipient is selected from sunscreens,fragrances, pigments, and antioxidants.

In certain aspects, the disclosure provides a dermatological compositioncomprising a dermatologically acceptable carrier, an alpha-adrenergicagent, and at least one permeation enhancer. In certain embodiments ofthe dermatological composition, the permeation enhancer increases skinpermeation of the alpha-adrenergic agent by about 2-fold or greater. Incertain embodiments of the dermatological composition, the permeationenhancer increases skin permeation of the alpha-adrenergic agent byabout 3-fold or greater. In certain embodiments of the dermatologicalcomposition, the permeation enhancer increases skin permeation of thealpha-adrenergic agent by about 0.5 mm or more. In certain embodimentsof the dermatological composition, the permeation enhancer increasesskin permeation of the alpha-adrenergic agent by about 1.0 mm or more.In certain embodiments of the dermatological composition, thealpha-adrenergic permeates through the skin and septal fat pad tocontact Müller's muscle. In certain embodiments of the dermatologicalcomposition, the permeation enhancer is selected from alcohols,sulfoxides, azones, pyrrolidones, ureas, alkyl-N,N-disubstitutedaminoacetals, propylene glycol, surfactants, terpenes, terpenoids, fattyacids, esters, cyclodextrins, and any combination thereof. In certainembodiments of the dermatological composition, the permeation enhanceris selected from ethanol, propylene glycol,dodecyl-N,N-dimethyl-aminoacetate, ethylacetate, azone, sodium dodecylsulfate, d-limonene, oleic acid, 1,3-diphenyl-urea,N-methyl-2-pyrrolidone, beta-cyclodextrin, dimethylsulfoxide, and anycombination thereof. In certain embodiments of the dermatologicalcomposition, the composition further comprises one or more cosmeticexcipients.

In certain aspects, the disclosure provides a dermatological compositioncomprising an alpha-adrenergic agent, at least one dermatologicallyacceptable carrier, and at least one cosmetic excipient selected fromsunscreens, fragrances, pigments, and antioxidants. In certainembodiments of the dermatological composition, the dermatologicallyacceptable carrier is selected from a lotion, an oil, a cream, a butter,a gel, an ointment, a spray, a milk, and a powder. In certainembodiments of the dermatological composition, the alpha-adrenergicagent is selected from naturally occurring or synthetic alpha-adrenergicagents. In certain embodiments of the dermatological composition, thealpha-adrenergic agent is selected from an alpha-1 agonist and analpha-2 agonist. In certain embodiments of the dermatologicalcomposition, the alpha-adrenergic agent is selected from amidephrine,anisodamine, anisodine, chloroethylclonidine, cirazoline,desvenlafaxine, dipivefrine, dopamine, ephedrine, epinephrine(adrenaline), etilefrine, ethylnorepinephrine, 5-fluronorepinephrine,6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol,methoxamine, methyldopa, midodrine, naphazoline, norepinephrine(noradrenaline), octopamine, oxymetazoline, phenylephrine,phenylpropanolamine, pseudoephedrine, synephrine, tetrahydrozoline,xylometazoline,6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole,A-61603(N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide),salts of any one thereof, and any combination thereof.

In certain embodiments of the dermatological composition, thealpha-adrenergic agent is oxymetazoline or a salt thereof. In certainembodiments of the dermatological composition, the alpha-adrenergicagent is oxymetazoline. In certain embodiments of the dermatologicalcomposition, the alpha-adrenergic agent is not oxymetazoline. In certainembodiments of the dermatological composition, the composition comprisesfrom about 0.5 to about 4 mg of the alpha-adrenergic agent per dose. Incertain embodiments of the dermatological composition, the compositioncomprises from about 0.5 μg to about 2 mg of the alpha-adrenergic agentper dose.

Also disclosed herein is a controlled-release dermatologicalcomposition, comprising an alpha-adrenergic agent and a delivery systemwhich controls the release of the alpha-adrenergic agent. In certainembodiments of the controlled-release dermatological composition, thecomposition is selected from a sustained-release composition, aprolonged-release composition, a pulsatile-release composition, and adelayed-release composition. In certain embodiments of thecontrolled-release dermatological composition, the delivery system isselected from polymer-based systems, porous matrices, hydrogel releasesystems, and peptide-based systems. In certain embodiments of thecontrolled-release dermatological composition, the composition is asustained-release composition. In certain embodiments of thecontrolled-release dermatological composition, the composition isformulated for administration to the exterior surface of the eyelid. Incertain embodiments of the controlled-release dermatologicalcomposition, the composition comprises from about 0.2 μg to about 6 mgof an alpha-adrenergic agent per dose. In certain embodiments of thecontrolled-release dermatological composition, the composition comprisesfrom about 0.5 μg to about 4 mg of an alpha-adrenergic agent per dose.In certain embodiments of the controlled-release dermatologicalcomposition, the composition comprises from about 0.5 μg to about 3 mgof an alpha-adrenergic agent per dose.

In certain embodiments of the controlled-release dermatologicalcomposition, the composition is formulated as a lotion, a cream, abutter, a gel, an ointment, a spray, a milk, or a powder. In certainembodiments of the controlled-release dermatological composition, thecomposition further comprises at least one dermatologically acceptablecarrier. In certain embodiments of the controlled-release dermatologicalcomposition, the composition further comprises one or more cosmeticexcipients selected from sunscreens, fragrances, pigments, andantioxidants.

In certain embodiments of the controlled-release dermatologicalcomposition, the alpha-adrenergic agent is selected from naturallyoccurring or synthetic alpha-adrenergic agents. In certain embodimentsof the controlled-release dermatological composition, thealpha-adrenergic agent is selected from an alpha-1 agonist and analpha-2 agonist. In certain embodiments of the controlled-releasedermatological composition, the alpha-adrenergic agent is selected fromamidephrine, anisodamine, anisodine, chloroethylclonidine, cirazoline,desvenlafaxine, dipivefrine, dopamine, ephedrine, epinephrine(adrenaline), etilefrine, ethylnorepinephrine, 5-fluronorepinephrine,6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol,methoxamine, methyldopa, midodrine, naphazoline, norepinephrine(noradrenaline), octopamine, oxymetazoline, phenylephrine,phenylpropanolamine, pseudoephedrine, synephrine, tetrahydrozoline,xylometazoline,6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole,A-61603(N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide),salts of any one thereof, and any combination thereof. In certainembodiments of the controlled-release dermatological composition, thealpha-adrenergic agent is oxymetazoline or a salt thereof.

Also disclosed herein is a method for treating ptosis of an eye of asubject in need thereof, comprising administering a compositioncomprising an alpha-adrenergic agent to the exterior surface of theeyelid of said eye of the subject. In certain embodiments of the methodfor treating ptosis, the composition is administered once, twice, orthree times per day. In certain embodiments of the method for treatingptosis, the composition is selected from any one of the eyeshadow, thedermatological, or the controlled-release dermatological compositionsdescribed herein. In certain embodiments of the method for treatingptosis, the composition is not administered to the eyeball.

Also disclosed herein is a method for cosmetic therapy of an eye of asubject, comprising administering a composition comprising analpha-adrenergic agent to the exterior surface of the eyelid of said eyeof the subject. In certain embodiments of the method for cosmetictherapy, the composition is administered once, twice, or three times perday. In certain embodiments of the method for cosmetic therapy, thecomposition is selected from any one of the eyeshadow, thedermatological, or the controlled-release dermatological compositionsdescribed herein. In certain embodiments of the method for cosmetictherapy, the composition is not administered to the eyeball.

Also disclosed herein is a method for increasing the vertical separationof the upper and lower eyelids of an eye of a subject, comprisingadministering a composition comprising an effective amount of analpha-adrenergic agent to the exterior surface of the eyelid of said eyeof the subject. In certain embodiments of the method for increasing thevertical separation of the upper and lower eyelids, the method increasesthe vertical separation of the upper and lower eyelids by about 10percent or more relative to the separation of the upper and lowereyelids prior to said administration. In certain embodiments of themethod for increasing the vertical separation of the upper and lowereyelids, the composition is selected from any one of the eyeshadow, thedermatological, or the controlled-release dermatological compositionsdescribed herein. In certain embodiments of the method for increasingthe vertical separation of the upper and lower eyelids, the subject doesnot have ptosis. In certain embodiments of the method for increasing thevertical separation of the upper and lower eyelids, the composition isnot administered to the eyeball.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION

The disclosure provides compositions and uses of alpha-adrenergicagents. In certain embodiments, the compositions of the disclosurecomprise an alpha-adrenergic agent and are suitable for topical,transdermal, or parenteral administration. In particular embodiments,the disclosure provides controlled-release compositions ofalpha-adrenergic agents for topical, transdermal, or parenteraladministration. In particular embodiments, the alpha-adrenergic agent isan alpha-adrenergic agonist such as oxymetazoline.

The compositions of the disclosure may be used as an alternative toblepharoplasty for treating ptosis of a subject. In certain embodiments,the compositions of the disclosure are used to increase the verticalseparation of the upper and lower eyelid of a subject or improve thevisual axis of a subject without the need for an invasive surgicalprocedure. In particular embodiments, the composition is administered toa subject who does not suffer from ptosis. Compositions of thedisclosure may be used for cosmetic purposes, such as to improve theappearance of the eyes.

In certain embodiments, the disclosure provides compositions, e.g.,cosmetic compositions, for topical administration to the exteriorsurface of the eyelid, or any portion thereof, wherein the compositioncomprises an agent that stimulates Müller's muscle. Agents thatstimulate Müller's muscle are known in the art and include, for example,alpha-adrenergic agents.

Alpha-Adrenergic Agents

In certain embodiments, the disclosure provides alpha-adrenergic agentswhich are compounds that modulate alpha-adrenergic receptors.Alpha-adrenergic agents of the disclosure may be selected from naturallyoccurring or synthetic alpha-adrenergic agents. In particularembodiments, the disclosure provides alpha-adrenergic agents thatagonize one or more of alpha-1 and alpha-2 adrenergic receptors. Incertain embodiments, the alpha-adrenergic agent agonizes alpha-1 andalpha-2 adrenergic receptors. In particular embodiments, thealpha-adrenergic agent agonizes alpha-1 and alpha-2 adrenergic receptorsand is selected from a compound other than oxymetazoline. In particularembodiments, the disclosure provides alpha-adrenergic agents thatantagonize one or more of alpha-1 and alpha-2 adrenergic receptors.

In certain embodiments, the alpha-adrenergic agent agonizes alpha-1adrenergic receptors. In certain embodiments, the alpha-adrenergic agentselectively agonizes alpha-1 adrenergic receptors. In certainembodiments, the alpha-adrenergic agent agonizes alpha-2 adrenergicreceptors. In certain embodiments, the alpha-adrenergic agent partiallyagonizes alpha-1 or alpha-2 adrenergic receptors. In certainembodiments, the alpha-adrenergic agonist is oxymetazoline. Inparticular embodiments, the alpha-adrenergic agent selectively agonizesalpha-1 adrenergic receptors and partially agonizes alpha-2 adrenergicreceptors and is selected from a compound other than oxymetazoline.

The term “agonist,” or a compound that “agonizes”, as used herein,generally refers to a compound that binds to a specific receptor andtriggers a response in the cell. An agonist generally mimics the actionof an endogenous ligand that binds to the same receptor.

The term “antagonist,” as used herein, refers to a molecule such as acompound, which diminishes, inhibits, or prevents a cellular response toa receptor activated by an agonist. Antagonists can include, but are notlimited to, competitive antagonists, non-competitive antagonists,uncompetitive antagonists, partial agonists and inverse agonists.Competitive antagonists can reversibly bind to receptors at the samebinding site (active site) as the endogenous ligand or agonist, withoutnecessarily activating the receptor. Non-competitive antagonists (alsoknown as allosteric antagonists) can bind to a distinctly separatebinding site from the agonist, exerting their action to that receptorvia the other binding site. Non-competitive antagonists generally do notcompete with agonists for binding. Binding of a non-competitiveantagonist to the receptor may result in a decreased affinity of anagonist to that receptor. Alternatively, binding of a non-competitiveantagonist to a receptor may prevent a conformational change in thereceptor required for agonist-mediated receptor activation.Non-competitive antagonists may require receptor activation by anagonist before they can bind to a separate allosteric binding site.

A “partial agonist” or a compound that “partially agonizes” refers tocompounds which, at a given receptor, might differ in the amplitude ofthe functional response that they elicit after maximal receptoroccupancy. Although they are agonists, partial agonists can act as acompetitive antagonist if co-administered with a full agonist, as itcompetes with the full agonist for receptor occupancy and producing anet decrease in the receptor activation observed with the full agonistalone.

A “full agonist” or a compound that “fully agonizes” an alpha-adrenergicreceptor, refers to a compound that activates a receptor producing fullefficacy at that receptor.

As used herein, the term “selectively” agonize, refers to the ability ofa compound described herein to agonize a target receptor with greateraffinity than non-target receptors. Methods for determining whether acompound selectively agonizes alpha-1 or alph-2 adrenergic receptors arewell known (e.g., A. Megans et al. Eur. J. Pharm. V. 129, I. 1-2, p57-64 (1996)).

In certain embodiments, alpha-adrenergic agonists are selected fromlong-acting alpha-adrenergic agents and short-acting alpha-adrenergicagonists. As used herein, a “long-acting alpha-adrenergic agonist” is analpha adrenergic agonist with a systemic half-life in normal adulthumans of greater than three hours. Long-acting alpha adrenergicagonists include, without limitation, oxymetazoline, methoxamine,naphazoline, tetrahydrozoline, xylometazoline, and apraclonidine (alsoknown as Iopidine®). In certain embodiments, the long-actingalpha-adrenergic agonist is oxymetazoline, with a reported half-life of5 to 6 hours. In one embodiment, the long-acting alpha-adrenergicagonist is a pharmaceutically acceptable salt of the long-actingalpha-adrenergic agonist. In certain embodiments, the long-actingalpha-adrenergic agonist is oxymetazoline or a pharmaceuticallyacceptable salt thereof, e.g., oxymetazoline hydrochloride.

As used herein, a “short-acting alpha-adrenergic agonist” is analpha-adrenergic agonist with a systemic half-life in normal adulthumans of less than or equal to three hours. Short-actingalpha-adrenergic agonists include, without limitation, phenylephrine andbrimonidine. In one embodiment the short-acting alpha-adrenergic agonistis a pharmaceutically acceptable salt of the short-actingalpha-adrenergic agonist. In certain embodiments, the short-actingalpha-adrenergic agonist is phenylephrine or a pharmaceuticallyacceptable salt thereof, e.g., phenylephrine hydrochloride.

In certain embodiments, the alpha-adrenergic agonist selectivelyagonizes alpha-1A adrenergic receptors. In certain embodiments, thealpha-adrenergic agonist selectively agonizes alpha-1B adrenergicreceptors. In certain embodiments, the alpha-adrenergic agonistselectively agonizes alpha-1D adrenergic receptors. In certainembodiments, the alpha-adrenergic agonist selectively agonizes alpha-2Aadrenergic receptors. In certain embodiments, the alpha-adrenergicagonist selectively agonizes alpha-2B adrenergic receptors. In certainembodiments, the alpha-adrenergic agonist selectively agonizes alpha-2Cadrenergic receptors.

In certain embodiments, the alpha-1 adrenergic agonist is selected fromamidephrine, anisodamine, anisodine, chloroethylclonidine, cirazoline,desvenlafaxine, dipivefrine, dopamine, ephedrine, epinephrine(adrenaline), etilefrine, ethylnorepinephrine, 5-fluronorepinephrine,6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol,methoxamine, methyldopa, midodrine, naphazoline, norepinephrine(noradrenaline), octopamine, oxymetazoline, phenylephrine,phenylpropanolamine, pseudoephedrine, synephrine, tetrahydrozoline,xylometazoline,6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole,A-61603(N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide),a salt of any one thereof, and any combination thereof. In certainembodiments, the alpha-1 adrenergic agonist is oxymetazoline or a saltthereof.

In certain embodiments, the alpha-1 adrenergic agonist is selected fromamidephrine, anisodamine, anisodine, chloroethylclonidine, cirazoline,desvenlafaxine, dipivefrine, dopamine, ephedrine, epinephrine(adrenaline), etilefrine, ethylnorepinephrine, 5-fluronorepinephrine,6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol,methoxamine, methyldopa, midodrine, naphazoline, norepinephrine(noradrenaline), octopamine, phenylephrine, phenylpropanolamine,pseudoephedrine, synephrine, tetrahydrozoline, xylometazoline,6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole,A-61603(N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide),a salt of any one thereof, and any combination thereof.

In certain embodiments, the alpha-adrenergic agonist is a selectivealpha-1A adrenergic agonist. In some embodiments, the alpha-1A selectiveadrenergic agonist is6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoleor A-61603(N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide).

In certain embodiments, the alpha-adrenergic agent is an alpha-2adrenergic agonist. In certain embodiments, the alpha-2 adrenergicagonist is selected from agmatine, amitraz, apraclonidine (lopidine),brimonidine, cannabigerol, cannabivarin, clonidine, detomidine,dexmedetomidine, dihydroergotamine, dipivefrine, dopamine, ephedrine,ergotamine, epinephrine (adrenaline), esproquin, etilefrin,ethylnorepinephrine, fadolmidine, 6-fluoronorepinephrine, guanabenz,guanfacine, guanoxabenz, levonordefrin, lofexidine, marsanidine,7-Me-marsanidine, medetomidine, methamphetamine, methyldopa, mivazerol,naphazoline, 4-NEMD (4-(1-naphthalen-1-ylethyl)-1H-imidazole),(R)-3-nitrobiphenyline, norepinephrine (noradrenaline),phenylpropanolamine, piperoxan, pseudoephedrine, rilmenidine,romifidine, talipexole, tetrahydrozoline, tizanidine, tolonidine,urapidil, xylazine, xylometazoline, a salt of any one thereof, and anycombination thereof.

The compositions described herein may include at least onealpha-adrenergic agent as an active ingredient in free-acid or free-baseform, or in a pharmaceutically acceptable salt form. Included in thepresent disclosure are salts, particularly pharmaceutically acceptablesalts, of the alpha-adrenergic agents herein. The alpha-adrenergicagents of the disclosure that possess a sufficiently acidic, asufficiently basic, or both functional groups, can react with any of anumber of inorganic bases, and inorganic and organic acids, to form asalt. Alternatively, compounds that are inherently charged, such asthose with a quaternary nitrogen, can form a salt with an appropriatecounterion, e.g., a halide such as bromide, chloride, or fluoride,particularly bromide.

The alpha-adrenergic agents described herein may in some cases exist asdiastereomers, enantiomers, or other stereoisomeric forms. The compoundspresented herein include all diastereomeric, enantiomeric, and epimericforms as well as the appropriate mixtures thereof. Separation ofstereoisomers may be performed by chromatography or by the formingdiastereomeric and separation by recrystallization, or chromatography,or any combination thereof (Jean Jacques, Andre Collet, Samuel H. Wilen,“Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc.,1981, herein incorporated by reference for this disclosure).Stereoisomers may also be obtained by stereoselective synthesis.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).Active metabolites of these compounds having the same type of activityare included in the scope of the present disclosure. In addition, thecompounds described herein can exist in unsolvated as well as solvatedforms with pharmaceutically acceptable solvents such as water, ethanol,and the like. The solvated forms of the alpha-adrenergic agentspresented herein are also considered to be disclosed herein. In somesituations, the alpha-adrenergic agents may exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein.

In certain embodiments, the alpha-adrenergic agent may be a prodrug,e.g., wherein a hydroxyl in the parent compound is presented as anester, a carbonate, or carboxylic acid present in the parent compound ispresented as an ester. In certain such embodiments, the prodrug ismetabolized to the active parent compound in vivo, e.g., the ester ishydrolyzed to the corresponding hydroxyl, or acid.

Cosmetic and Pharmaceutical Compositions

In certain embodiments, provided herein are cosmetic and therapeuticcompositions comprising an agent that stimulates Müller's muscle, e.g.,an alpha-adrenergic agonist or a cosmetically or pharmaceuticallyacceptable salt, polymorph, solvate, prodrug, N-oxide or isomer thereof,and an excipient. In some embodiments, the alpha-adrenergic agents areformulated into pharmaceutical or cosmetic compositions. Cosmetic orpharmaceutical compositions may be formulated in a conventional mannerusing one or more pharmaceutically acceptable inactive ingredients thatfacilitate processing of the active compounds into preparations that canbe used pharmaceutically or cosmetically. Proper formulation isdependent upon the route of administration chosen. Exemplarycompositions of the disclosure include those found in Remington: TheScience and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference for such disclosure.

In certain embodiments, provided herein are pharmaceutical compositionsthat include an alpha-adrenergic agent as described herein and at leastone cosmetic or pharmaceutically acceptable excipient. In certainembodiments, the at least one cosmetic or pharmaceutically acceptableexcipient is selected from carriers, buffering agents, binders, fillingagents, suspending agents, disintegrating agents, dispersing agents,surfactants, lubricants, diluents, solubilizers, plasticizers,stabilizers, wetting agents, anti-foaming agents, antioxidants,preservatives, pigments, or a combination thereof. In certainembodiments, the at least one cosmetic or pharmaceutically acceptableexcipient is a cosmetic excipient, such as those described herein.

In certain embodiments, compositions of the disclosure include two ormore alpha-adrenergic agents such as two alpha-adrenergic agents.

The compositions described herein are administered to a subject byappropriate administration routes, including but not limited to,parenteral (e.g., intravenous, subcutaneous, intramuscular), topical, ortransdermal administration routes. The compositions described hereininclude, but are not limited to, aqueous liquid dispersions, liquids,gels, slurries, suspensions, self-emulsifying dispersions, solidsolutions, liposomal dispersions, aerosols, powders, immediate releaseformulations, controlled-release compositions, lyophilized formulations,delayed-release formulations, extended-release formulations,pulsatile-release formulations, multiparticulate formulations, and mixedimmediate and controlled-release compositions.

Compositions including an alpha-adrenergic agent described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping, or compressionprocesses.

As will be understood by those skilled in the art, the most appropriatemethod of administering an alpha-adrenergic agent to a subject isdependent on a number of factors. In various embodiments, thealpha-adrenergic agent is administered topically to the eye or to theeyelid. In some embodiments, the alpha-adrenergic agent is administeredtopically to the eyelid such as to the exterior surface of the eyelid.In certain embodiments, the alpha-adrenergic agent is formulated forcosmetic application to the eyelid and may include additional agentssuch as sunscreens, vitamins, moisturizers (e.g., hyaluronic acid),antioxidants, pigments, natural oils or butters, or essential fattyacids. In certain embodiments, an alpha-adrenergic agent is formulatedas a lotion or cosmetic, e.g., eyeshadow or eyeliner, for topicaladministration to the exterior surface of the eyelid.

In some embodiments, the alpha-adrenergic agent is administeredparenterally, such as injected into the eyelid. The alpha-adrenergicagent may be injected intravenously into the eyelid or the surroundingarea, such as injected into the angular vein. The alpha-adrenergic agentmay be administered subcutaneously, such as administered by subcutaneousinjection into the eyelid. In some embodiments, the alpha-adrenergicagent is administered intramuscularly, such as though injection intoMüller's muscle in the eyelid. In certain embodiments, thealpha-adrenergic agent is administered pre-septally, post-septally, orinto the post-septal fat pad.

Parenteral Formulation

In some embodiments, an agent that stimulates Müller's muscle, e.g., analpha-adrenergic agent, is administered parenterally, such as byinjection. Parenteral administration may involve bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The pharmaceutical composition described herein maybe in a form suitable for parenteral injection, such as a sterilesuspension, solution, or emulsion in oily or aqueous vehicles, and maycontain additional agents such as suspending, stabilizing, and/ordispersing agents.

Formulations for parenteral administration include aqueous solutions ofthe alpha-adrenergic agent in water-soluble form. Additionally,suspensions of the alpha-adrenergic agent may be prepared as appropriateoily injection suspensions. Suitable lipophilic solvents or vehiclesinclude fatty oils such as sesame oil; synthetic fatty acid esters, suchas ethyl oleate; triglycerides; or liposomes. Aqueous injectionsuspensions may contain substances which increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension may also contain suitablestabilizers or agents which increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use. In certain embodiments, systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions.

Formulations suitable for intramuscular, subcutaneous, or intravenousinjection may include physiologically acceptable sterile aqueous ornon-aqueous solutions, dispersions, suspensions or emulsions, andsterile powders for reconstitution into sterile injectable solutions ordispersions. Examples of suitable aqueous and non-aqueous carriers,diluents, solvents, or vehicles include water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor, and thelike), suitable mixtures thereof, vegetable oils (such as olive oil),and injectable organic esters such as ethyl oleate. Proper fluidity canbe maintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants.

Formulations suitable for subcutaneous injection may also containadditives such as preserving, wetting, emulsifying, and dispensingagents. Prevention of the growth of microorganisms can be ensured byvarious antibacterial and antifungal agents. It may also be desirable toinclude isotonic agents, such as sugars, sodium chloride, and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the use of agents delaying absorption, such as aluminummonostearate and gelatin.

For intravenous injections, an alpha-adrenergic agent may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer.

In various embodiments, the injectable composition comprises from about0.1 μg to about 4 mg of the alpha-adrenergic agent per dose. In certainembodiments, the injectable composition comprises from about 0.1 mg toabout 10 mg of the alpha-adrenergic agent per dose. In some embodimentsthe composition comprises about 0.1 mg, about 0.2 mg, about 0.3 mg,about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg,about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg,about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg,about 1.9 mg, about 2.0 mg, 2.1 mg, about 2.2 mg, about 2.3 mg, about2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about2.9 mg, about 3.0 mg, 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg,about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg,about 4.0 mg, 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about5.0 mg, 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg,about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg,6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, 7.1 mg,about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg,about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, 8.1 mg, about8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, 9.1 mg, about 9.2 mg,about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg,about 9.8 mg, about 9.9 mg, or about 10 mg of the alpha-adrenergic agentper dose. In certain embodiments, any two of the doses in this paragraphmay be combined to form a range of dosages included within thedisclosure, e.g., the injectable composition comprises from about 1.0 mgto about 9.0 mg of an alpha-adrenergic agent per dose.

In some embodiments, the injectable composition comprises from about 0.1mg to about 1 mg of the alpha-adrenergic agent per dose. In someembodiments, the injectable composition comprises from about 0.5 mg toabout 1 mg of the alpha-adrenergic agent per dose. In some embodiments,the injectable composition comprises from about 1 mg to about 3 mg ofthe alpha-adrenergic agent per dose. In some embodiments, the injectablecomposition comprises from about 3 mg to about 5 mg of thealpha-adrenergic agent per dose.

In some embodiments, the injectable composition comprises 0.5 mg orless, e.g., from about 0.05 mg to about 0.4 mg, of the alpha-adrenergicagent per dose. In some embodiments, the injectable compositioncomprises 1 mg or less, e.g., from about 0.05 mg to about 0.9 mg, of thealpha-adrenergic agent per dose. In some embodiments, the injectablecomposition comprises 2 mg or less, e.g., from about 0.05 mg to about1.9 mg, of the alpha-adrenergic agent per dose. In some embodiments, theinjectable composition comprises 4 mg or less, e.g., from about 0.05 mgto about 3.9 mg, of the alpha-adrenergic agent per dose. In someembodiments, the injectable composition comprises at least 0.5 mg of thealpha-adrenergic agent per dose. In some embodiments, the injectablecomposition comprises at least 1 mg of the alpha-adrenergic agent perdose. In some embodiments, the injectable composition comprises at least2 mg of the alpha-adrenergic agent per dose. In some embodiments, theinjectable composition comprises at least 4 mg of the alpha-adrenergicagent per dose.

In some embodiments, the injectable composition comprises from about 0.5μg to about 1 mg of the alpha-adrenergic agent per dose, e.g., fromabout 0.5 μg to about 10 μg, from about 0.5 μg to about 0.1 mg, fromabout 0.5 μg to about 0.5 mg, from about 10 μg to about 0.1 mg, fromabout 10 μg to about 0.5 mg, from about 0.1 mg to about 0.5 mg, or fromabout 0.1 mg to about 1 mg.

In various embodiments, a dose of the injectable composition is injecteddaily, weekly, or monthly as needed. In some embodiments, a dose of theinjectable composition is injected once a day, twice a day, or threetimes a day, as needed. In some embodiments, a dose of the injectablecomposition is injected every other day. In certain embodiments, a doseof the injectable composition is injected every three days, every fourdays, or every five days.

Topical/Transdermal Formulation

In some embodiments, the alpha-adrenergic agent is formulated into atopically administrable composition. In some embodiments, the topicalformulation is administered to the external surface of the eyelid. Insome embodiments, the alpha-adrenergic agent is formulated into atransdermal administrable composition. In some embodiments, thetransdermal formulation is administered to the external surface of theeyelid.

Topical Formulation

In certain embodiments, the alpha-adrenergic agent is administeredtopically to a subject. In certain embodiments, topical compositions ofthe disclosure are dermatological compositions and are applied to thesurface of the skin, e.g., exterior surface of the eyelid such as theupper eyelid. In some embodiments, the topical formulation comprises analpha-adrenergic agent and one or more excipients. In some embodiments,the topical formulation comprises a dermatologically acceptable carriersuch as a dermatologically acceptable carrier conventional in thecosmetic, pharmaceutical, or dermatological fields. In certainembodiments, compositions of the disclosure further comprise at leastone excipient. As used herein, the term “dermatologically acceptablecarrier” refers to vehicles, diluents, and carriers known in the art tobe suitable for use in dermatological compositions. A dermatologicallyacceptable carrier can further include adjuvants, additives, andexcipients that enhance the carrier's structure and function, includingbut not limited to buffers, preservatives, gelling agents, rheologicalmodifiers and stabilizers, moisturizers, and humectants. Suitablecomponents are those known in the art to be suitable for use in contactwith the skin of humans without undue toxicity, irritation, or allergicresponse. Suitable materials may be selected from the “Inventory ofingredients employed in cosmetic products,” provided in EuropeanCommission Decision 2006/257/EC of Feb. 9, 2006.

Dermatologically acceptable carriers may be in the form of aqueous,aqueous/alcoholic or oily solutions; powders; dispersions of the lotionor serum type; anhydrous or lipophilic gels; emulsions of liquid orsemi-liquid consistency, which are obtained by dispersion of a fattyphase in an aqueous phase (O/W) or conversely (W/O); or suspensions oremulsions of smooth, semi-solid or solid consistency of the cream or geltype. The dermatologically acceptable carrier may take the physical formof a liquid, lotion, cream, butter, gel, ointment, or powder. In certainembodiments, the dermatologically acceptable carrier is selected from acarrier acceptable for administration to the exterior surface of theeyelid.

Water-containing emulsions, in the form of lotions or creams may permitan effective amount of the composition to be applied to the area of skinin need of treatment, do not rapidly dry out, and maintain contact ofthe skin with the alpha-adrenergic agent for an extended period of time.By moisturizing and softening the stratum corneum, lotions and creamsalso improve the rate of penetration of the alpha-adrenergic agent intothe epidermis. In some embodiments, the lotion and cream compositionsaccording to the invention comprise water and an effective amount of anemulsifier.

In some embodiments, the compositions comprise a dermatologicallyacceptable oil. Suitable oils are well known in the cosmetic arts, andinclude but are not limited to grapeseed oil, olive oil, sweet almondoil, avocado oil, sesame oil, canola oil, jojoba oil, and the like, aswell as mineral oil and synthetic oils such as dimethicone. In someembodiments, the compositions comprise a semisolid triglyceride,including but not limited to shea butter, cocoa butter, illipe butter,mango butter, avocado butter or the like. In certain embodiments, thecompositions comprise silicone.

In some embodiments, the compositions comprise a stiffener, such asstearic acid or 12-hydroxystearic acid. The amount of the stiffener maybe varied depending on whether a lotion or cream is desired, forexample. In certain embodiments, the topical compositions comprisehyaluronic acid or a salt thereof.

In some embodiments, the compositions comprise an emulsifier in order touniformly incorporate water into the ointment, such as one or more ofemulsifying wax NF, glyceryl stearate, cetearyl alcohol, or sodiumstearoyl lactylate. In some embodiments, the compositions comprisehumectants, including but not limited to glycerin, sugar alcohols, oraloe vera gel.

In certain embodiments, the carrier may comprise a thickener. Exemplarythickeners are cross-linked polyacrylate materials available under thetrademark Carbopol. Gums may be employed such as xanthan, carrageenan,gelatin, karaya, pectin and locust beans gum. Under certaincircumstances the thickening function may be accomplished by a materialalso serving as a silicone or emollient.

In certain embodiments the dermatologically acceptable carrier comprisesa powder. Powders of the compositions may be selected from chalk, talc,kaolin, starch, mica, smectite clays, chemically modified magnesiumaluminum silicate, organically modified montmorillonite clay, hydratedaluminum silicate, fumed silica, aluminum starch octenyl succinate andmixtures thereof.

The compositions of the invention may include additives and adjuvantswhich are conventional in the cosmetic, pharmaceutical or dermatologicalfield, such as gelling agents, preservatives, antioxidants, solvents,fragrances, fillers, bactericides, odor absorbers, sunscreens, orpigments. The amounts of these various additives and adjuvants are thoseconventionally used in the field, and, for example, range from about0.01% to about 90% of the total weight of the composition. In particularembodiments, a composition of the disclosure comprises one or morecosmetic excipients suitable for administration to the exterior surfaceof the eyelid.

In certain embodiments, the compositions of the disclosure comprise anagent that stimulates Müller's muscle and at least one cosmeticexcipient. A “cosmetic excipient”, as used herein, refers to anexcipient which is used to enhance one or more cosmetic properties of acomposition, e.g., dermatological composition, described herein. Incertain embodiments, a cosmetic property is the appearance, the smell,the texture, the ease of application, etc., of the composition. Incertain embodiments, the cosmetic property is the effect of the use ofthe composition such as improving the appearance or texture of the skin,reducing the appearance of wrinkles, protecting the skin from radiation,covering up marks or blemishes on the skin, or any combination thereof.

An “eyeshadow composition”, as described herein, refers to a compositionsuitable for administration to the exterior surface of the eyelid. Aneyeshadow composition is not intended to be limited to any particulartype of composition or method of application and can include, forexample, liquids, creams, powders, etc., that are suitable forapplication, e.g., using an applicator, a finger, or a brush, etc., tothe exterior surface of an eyelid or any portion thereof. Eyeshadowcompositions of the disclosure may include one or more cosmeticexcipients.

In some embodiments, the compositions comprise an effective amount ofone or more preservatives, including but not limited to potassiumsorbate, citric acid, propylparaben, methylparaben, glycol, tocopherol,diazolidinyl urea, and imidazolidinyl urea. In some embodiments, thecompositions include any of the oils and triglycerides above, and mayfurther comprise a hydrocarbon base such as hard paraffin, softparaffin, microcrystalline wax, or ceresin wax. In some embodiments,non-hydrocarbon bases such as wool fat or beeswax are also employed.

In some embodiments, the composition comprises a sunscreen. In certainembodiments, the sunscreen is selected from zinc oxide, titaniumdioxide, octyl methoxycinnamate, octyl salicylate, avobenzone, menthylanthranilate, cinoxate, ecamsule, octyl salicylate, octylmehtoxycinnamate, sulisobenzone, oxybenzone, and combination thereof.

In certain embodiments, compositions of the disclosure comprise one ormore of the following: mica, PTFE, zinc stearate, silica, isoeicosane,polyisobutene, lauroyl lysine, dimethicone, boron nitride, polyethylene,phenoxyethanol, Nylon-12, caprylic/capric triglyceride, sorbic acid,sodium dehydroacetate, magnesium stearate, talc, ethylhexyl palmitate,ethylene/acrylic acid copolymer, poloxamer, synthetic wax, tin oxide,kaolin, triethylhexanoin, hydrogenated lecithin, tocopheryl acetate,caprylyl glycol, hexylene glycol, calcium sodium borosilicate,ethylhexylgycerin, synthetic sapphire, calcium aluminum borosilicate,C13-16 isoparaffin, octadecene, stearyl dimethicone, titanium dioxide CI77891, iron oxides CI 77491CI 77492CI 77499, ultramarines CI 77007,carmine CI 75470, manganese violet CI 77742, yellow 5 Lake CI 19140,ferric ferrocyanide CI 77510, bismuth oxychloride CI 77163, chromiumhydroxide green CI 77289, chromium oxide greens CI 77288, zinc oxide,blue 1 Lake CI 42090, ferric ammonium ferrocyanide CI 77510, bronzepowder, DC black No. 2 CI 77266, and red 40 Lake CI 16035.

In some embodiments, the alpha-adrenergic agent is formulated as aneyeshadow composition suitable for administration to the exteriorsurface of the eyelid, e.g., the upper eyelid. In some embodiments, theeyeshadow comprises a powder. Suitable powders generally comprise a dryparticulate matter that have a particles size of about 0.02 to about200, preferably about 0.5 to about 100 microns. In some embodiments, theparticulate matter is colored. Suitable powders that may be used ineyeshadow compositions include, for example, bismuth oxychloride,titanated mica, fumed silica, spherical silica, polymethylmethacrylate,micronized teflon, boron nitride, acrylate polymers, aluminum silicate,aluminum starch octenylsuccinate, bentonite, calcium silicate,cellulose, chalk, corn starch, diatomaceous earth, fuller's earth,glyceryl starch, hectorite, hydrated silica, kaolin, magnesium aluminumsilicate, magnesium carbonate, magnesium hydroxide, magnesium oxide,magnesium silicate, magnesium trisilicate, maltodextrin,montmorillonite, microcrystalline cellulose, rice starch, silica, talc,mica, titanium dioxide, zinc laurate, zinc myristate, zinc neodecanoate,zinc rosinate, zinc stearate, polyethylene, alumina, attapulgite,calcium carbonate, calcium silicate, dextran, kaolin, nylon, silicasilylate, silk powder, sericite, soy flour, tin oxide, titaniumhydroxide, trimagnesium phosphate, walnut shell powder, and mixturesthereof. In some embodiments, the powders are surface treated withlecithin, amino acids, mineral oil, silicone oil, or various otheragents either alone or in combination, to coat the powder surface andrender the particles hydrophobic in nature.

In some embodiments, powders of eyeshadow compositions described hereincomprise organic or inorganic pigments. Organic pigments may be selectedfrom aromatic compounds including azo, indigoid, triphenylmethane,anthraquinone, and xanthine dyes which are designated as D&C and FD&Cblues, browns, greens, oranges, reds, yellows, etc. Organic pigments maybe selected from insoluble metallic salts of certified color additives,referred to as the Lakes. Inorganic pigments include iron oxides,ultramarine and chromium or chromium hydroxide colors, and mixturesthereof. The percentage of pigments used in the powder component willdepend upon the type of cosmetic being formulated and is usually rangingfrom about 5 to about 50% of the total cosmetic composition. In someembodiments, the pigment to powder weight ratio ranges from about 1:20to about 20:1 or about 1:10 to about 1:2.

In some embodiments, the topical composition comprises from about 0.1 μgto about 5 mg of the alpha-adrenergic agent per dose. In someembodiments, the topical composition comprises from about 0.5 μg toabout 4 mg of the alpha-adrenergic agent per dose. In some embodiments,the topical composition comprises from about 1 μg to about 3 mg of thealpha-adrenergic agent per dose. In some embodiments, the topicalcomposition comprises from about 3 μg to about 5 mg of thealpha-adrenergic agent per dose.

In some embodiments, the topical composition comprises from about 0.5 μgto about 1 mg of the alpha-adrenergic agent per dose, e.g., from about0.5 μg to about 10 μg, from about 0.5 μg to about 0.1 mg, from about 0.5μg to about 0.5 mg, from about 10 μg to about 0.1 mg, from about 10 μgto about 0.5 mg, from about 0.1 mg to about 0.5 mg, or from about 0.1 mgto about 1 mg per dose.

In some embodiments, the topical composition comprises about 0.5 mg orless, e.g., from about 0.5 μg to about 0.4 mg, of the alpha-adrenergicagent per dose. In some embodiments, the topical composition comprisesabout 1 mg or less, e.g., from about 0.5 μg to about 0.9 mg, of thealpha-adrenergic agent per dose. In some embodiments, thetopical/transdermal composition comprises about 2 mg or less, e.g., fromabout 0.5 μg to about 1.9 mg, of the alpha-adrenergic agent per dose. Insome embodiments, the topical composition comprises about 4 mg or less,e.g., from about 0.5 μg to about 3.9 mg, of the alpha-adrenergic agentper dose.

In some embodiments, the topical composition comprises at least about0.5 μg of the alpha-adrenergic agent per dose. In some embodiments, thetopical composition comprises at least about 1 μg of thealpha-adrenergic agent per dose. In some embodiments, the topicalcomposition comprises at least about 2 μg of the alpha-adrenergic agentper dose. In some embodiments, the topical composition comprises atleast about 4 μg of the alpha-adrenergic agent per dose.

In various embodiments, a dose of the topical composition is applied tothe exterior surface of the eyelid of the subject as needed. In someembodiments, a dose of the topical composition is applied once a day,twice a day, three times a day, four times a day, five times a day, sixtimes a day, seven times a day, eight times a day, nine times a day, orten times a day. A dose of the topical composition may be applied to aneyelid of a subject from one to ten times a day, such as from one tofive times a day. In certain embodiments, a dose of the topicalcomposition is applied once every two days, once every three days, onceevery four days, once every five days, once every six days, or even onceevery seven days.

In certain embodiments, the topical composition providessustained-release of the alpha-adrenergic agent. In certain embodiments,the topical composition comprises a delivery system which controls therelease of the alpha-adrenergic agent to the subject. In variousembodiments, the release of the alpha-adrenergic agent is sustained overa period of 4 hours or more after application, 5 hours or more afterapplication, 6 hours or more after application, 7 hours or more afterapplication, 8 hours or more after application, 9 hours or more afterapplication, 10 hours or more after application, 11 hours or more afterapplication, 12 hours or more after application, 14 hours or more afterapplication, 16 hours or more after application, 18 hours or more afterapplication, 20 hours or more after application, 22 hours or more afterapplication or even 24 hours or more after application.

Transdermal Formulations

In some embodiments, the alpha-adrenergic agent is administered viatransdermal formulation. In certain embodiments a transdermalformulation of the disclosure is a topical formulation, as described inthe preceding section, with one or more additional excipients whichfacilitate transport across the skin. Transdermal formulations describedherein may be administered using a variety of devices including but notlimited to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683,3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073,3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211,4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280,5,869,090, 6,923,983, 6,929,801 and 6,946,144.

The transdermal dosage forms described herein incorporate certainpharmaceutically acceptable excipients which are conventional in theart. Transdermal formulations of the disclosure may comprise one or moreof the carriers, excipients, and additives discussed in the precedingsection. In one embodiment, the transdermal formulations describedherein comprise an alpha-adrenergic agent and a permeation enhancer. Inaddition, transdermal formulations can include additional componentssuch as, but not limited to, aqueous adjuvant, gelling agents, creamsand ointment bases, and the like. In some embodiments, the transdermalformulation can further include a woven or non-woven backing material toenhance absorption and prevent the removal of the transdermalformulation from the skin. In other embodiments, the transdermalformulations described herein can maintain a saturated or supersaturatedstate to promote diffusion into the skin.

The term “permeation enhancer” refers to a substance used to modify,generally to increase, the rate of permeation through skin or other bodytissue of the alpha-adrenergic agent in the composition. Most knownpermeation enhancers fall into the following categories: alcohols(ethanol, pentanol, benzyl alcohol, lauryl alcohol, propylene glycolsand glycerol), fatty acids (oleic acid, linoleic acid, valeric acid andlauric acid), amines (diethanolamine and triethanolamine), esters(isopropyl palmitate, isopropyl myristate and ethyl acetate), amides(1-dodecylazacycloheptane-2-one [Azone®], urea, dimethylacetamide,dimethylformamide and pyrrolidone derivatives), hydrocarbons (alkanesand squalene), surfactants (sodium laureate, cetyltrimethylammoniumbromide, Brij®, Tween® and sodium cholate), terpenes (D-limonene,carvone and anise oil), sulfoxides (dimethyl sulfoxide) andphospholipids (lecithin). Other examples of permeation enhancer includeamine oxides, unsaturated fatty acids, alpha-terpineol, and sorbitanmonooleate. Amine oxides include, for example, lauramine oxide and2-hexadecyldimethylamine oxide. Unsaturated fatty acids include, forexample, oleic acid, linoleic acid, and linolenic acid. Sorbitan estersinclude, for example, sorbitan monooleate, sorbitan laurate, andsorbitan stearate. Isopropyl myristate and lauroglycol are also suitablefor use as permeation enhancers. In some embodiments, a permeationenhancer of the compositions described herein, enhances permeation of analpha-adrenergic agent into healthy skin, e.g., skin not effected bydiseases or conditions such as rosacea, eczema, acne, psoriasis, etc. Ingeneral, healthy skin forms a formidable barrier to entry forpharmaceutical agents, such as alpha-adrenergic agents, whereasunhealthy skin is more permeable to such agents. Permeation enhancersthat may enhance permeation of alpha-adrenergic agents into unhealthyskin may be insufficient to affect permeation of such agents, orpermeation of such agents to the same depth, into healthy skin. Incertain embodiments, a permeation enhancer of the compositions describedherein may be characterized by significant permeation of analpha-adrenergic agent into healthy skin, e.g., about 2-fold or more,about 3-fold or more, about 4-fold, or more about 5-fold or more, about6-fold or more permeation relative to the permeation of such agentwithout a permeation enhancer. In certain embodiments, a permeationenhancer of the compositions described herein may permit permeationthrough the stratum corneum and septal fat pad to contact Müller'smuscle. In certain embodiments, a permeation enhancer of thecompositions described herein enables permeation of an alpha-adrenergicagent, e.g., oxymetazoline or a salt thereof, of up to about 3 mm, suchas up to about 2.5 mm, such as up to about 2 mm deep into healthy skin.

In certain embodiments, the amount of permeation enhancer in thecompositions of the disclosure is diminished relative to the amount usedin compositions for unhealthy skin. For example, a composition of thedisclosure may have up to about 10% less, up to about 20% less, up toabout 30% less, up to about 40% less, up to about 50% less, up to about60% less, up to about 70%, or even up to about 80% less than the amountof permeation enhancer needed to permeate the same agent to the samedepth in unhealthy skin.

Examples of permeation enhancers are found in Pathan et al. (“ChemicalPenetration Enhancers for Transdermal Drug Delivery Systems” TropicalJournal of Pharmaceutical Research, April 2009; 8 (2): 173-179); Som etal. (“Status of Surfactants as Penetration Enhancers in Transdermal DrugDelivery” J Pharm Bioallied Sci. 2012; 4(1): 2-9); and Trommer at al.(“Overcoming the Stratum Corneum: The Modulation of Skin Penetration”Skin Pharmacol Physiol 2006; 19:106-121) all of which incorporated byreference in their entireties. In certain embodiments, the skinpermeation is measured as shown in Franz T J “Percutaneous absorption.On the relevance of in vitro data” J. Invest. Dermatol 1975, 64:190-195,which is incorporated by reference in its entirety. In the experimentalconfiguration for measuring skin permeation, a piece of skin (about 2.5cm by 2.5 cm square) is mounted over a receptor well, fully filled witha solvent to ensure uniform contact with the underside of the skinpiece. Clamped on top of the skin piece is a donor well into which thetest formulation is introduced. Fluid samples can be abstracted from thereceptor at given time intervals, and then analyzed for theconcentration of the active. Retention of the active agent in the skin,or in the separate epidermal and dermal skin compartments, is thenmeasured. Animal models utilizing pig skin are used to measure thepermeation of active agents (See for example: Barbero et al. 2009 “Pigand guinea pig skin as surrogates for human in vitro penetrationstudies: a quantitative review” Toxicol. In Vitro 23, 1-13; Godin et al.2007 “Transdermal skin delivery: predictions for humans from in vivo, exvivo and animal models” Adv. Drug Deliv. Rev. 59, 1152-1161; Mahl et al.2006 “The minipig in dermatotoxicology: methods and challenges” Exp.Toxicol. Pathol. 57, 341-345; Yu et al. 2013 “Topical skin targetingeffect of penetration modifiers on hairless mouse skin, pig abdominalskin and pig ear skin” Drug Delivery Vol. 22, Iss. 8, 2015; and Simon etal. “The pig as an experimental animal model of per-cutaneous permeationin man: qualitative and quantitative observations—an overview” SkinPharmacol. Appl. Skin Physiol. 200, 13, 229-234; all of whichincorporated by reference in their entireties).

The permeation enhancer should be present in an amount sufficient toallow permeation of a sufficient amount of the alpha-adrenergic agentacross the skin so as to have a desired therapeutic effect. The amountof permeation enhancer is typically less than about 40% by weight of thetotal composition, or less than about 39%, less than about 38%, lessthan about 37%, less than about 36%, less than about 35%, less thanabout 34%, less than about 33%, less than about 32%, less than about31%, less than about 30%, less than about 29%, less than about 28%, lessthan about 27%, less than about 26%, less than about 25%, less thanabout 24%, less than about 23%, less than about 22%, less than about21%, less than about 20%, less than about 19%, less than about 18%, lessthan about 17%, less than about 16%, less than about 15%, less thanabout 14%, less than about 13%, less than about 12%, less than about11%, or less than about 10% by weight of the total composition.

In some embodiments, formulations suitable for transdermaladministration of an alpha-adrenergic agent employ transdermal deliverydevices and transdermal delivery patches. Such patches may beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents. The rate of absorption can be slowed by usingrate-controlling membranes or by trapping the compound within a polymermatrix or gel. For example, transdermal devices are in the form of abandage comprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound to the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

In some embodiments, the transdermal composition comprising analpha-adrenergic agent is incorporated into different make-up productssuch as make-up foundation, fluid foundations and compact foundations,make-up removal lotions, make-up removal milks, eyeshadows, and powders.

In some embodiments, the transdermal composition comprises from about0.1 μg to about 1 mg of the alpha-adrenergic agent per dose. In someembodiments, the transdermal composition comprises from about 0.5 μg toabout 1 mg of the alpha-adrenergic agent per dose. In some embodiments,the transdermal composition comprises from about 1 μg to about 3 mg ofthe alpha-adrenergic agent per dose. In some embodiments, thetransdermal composition comprises from about 3 μg to about 5 mg of thealpha-adrenergic agent per dose.

In some embodiments, the transdermal composition comprises from about0.5 μg to about 1 mg of the alpha-adrenergic agent per dose, e.g., fromabout 0.5 μg to about 10 μg, from about 0.5 μg to about 0.1 mg, fromabout 0.5 μg to about 0.5 mg, from about 10 μg to about 0.1 mg, fromabout 10 μg to about 0.5 mg, from about 0.1 mg to about 0.5 mg, or fromabout 0.1 mg to about 1 mg.

In some embodiments, the transdermal composition comprises about 0.5 mgor less, e.g., from about 0.5 μg to about 0.4 mg, of thealpha-adrenergic agent per dose. In some embodiments, the transdermalcomposition comprises about 1 mg or less, e.g., from about 0.5 μg toabout 0.9 mg, of the alpha-adrenergic agent per dose. In someembodiments, the topical/transdermal composition comprises about 2 mg orless, e.g., from about 0.5 μg to about 1.9 mg, of the alpha-adrenergicagent per dose. In some embodiments, the transdermal compositioncomprises about 4 mg or less, e.g., from about 0.5 μg to about 3.9 mg,of the alpha-adrenergic agent per dose.

In some embodiments, the transdermal composition comprises at leastabout 0.5 μg of the alpha-adrenergic agent per dose. In someembodiments, the transdermal composition comprises at least about 1 μgof the alpha-adrenergic agent per dose. In some embodiments, thetransdermal composition comprises at least about 2 μg of thealpha-adrenergic agent per dose. In some embodiments, thetopical/transdermal composition comprises at least about 4 μg of thealpha-adrenergic agent per dose.

In various embodiments, a dose of the transdermal composition is appliedto the exterior surface of the eyelid of the subject as needed. In someembodiments, a dose of the transdermal composition is applied once aday, twice a day, three times a day, four times a day, five times a day,six times a day, seven times a day, eight times a day, nine times a day,or ten times a day. A dose of the topical/transdermal composition may beapplied to an eyelid of a subject from one to ten times a day, such asfrom one to five times a day. In certain embodiments, a dose of thetransdermal composition is applied once every two days, once every threedays, once every four days, once every five days, once every six days,or even once every seven days.

In certain embodiments, the transdermal composition providessustained-release of the alpha-adrenergic agent. In certain embodiments,the transdermal composition comprises a delivery system which controlsthe release of the alpha-adrenergic agent to the subject. In variousembodiments, the release of the alpha-adrenergic agent is sustained overa period of 4 hours or more after application, 5 hours or more afterapplication, 6 hours or more after application, 7 hours or more afterapplication, 8 hours or more after application, 9 hours or more afterapplication, 10 hours or more after application, 11 hours or more afterapplication, 12 hours or more after application, 14 hours or more afterapplication, 16 hours or more after application, 18 hours or more afterapplication, 20 hours or more after application, 22 hours or more afterapplication or even 24 hours or more after application.

Controlled-Release Compositions

In some embodiments, the alpha-adrenergic agent is administered to asubject as a controlled-release composition. In certain embodiments, acontrolled-release composition comprises an alpha-adrenergic agent and adelivery system which controls the release of the alpha-adrenergicagent. In certain embodiments, the controlled-release compositioncomprises a delivery system and any of the alpha-adrenergic agentcompositions described herein. In certain embodiments, acontrolled-release composition comprises a topical or transdermalformulation, described in the preceding sections. Examples of deliverysystems include, e.g., polymer-based systems such as implants orinserts; porous matrices; hydrogel release systems; transdermal patches;peptide-based systems; and contact lenses.

In some embodiments, the delivery system is a polymer-based implant. Apolymer-based implant, such as a bioerodible implant, may be implantedinto the eyelid or surrounding area and the polymer-based implantprovides controlled-release of the alpha-adrenergic agent over a periodof time. In some embodiments, the polymer-based implant is implantedsurgically. In some embodiments, the implant is injected without theneed for surgery. The polymer-based implant may be implantedsubcutaneously or intramuscularly. In certain embodiments, thepolymer-based implant may be implanted in close proximity to Müller'smuscle, such as within about one millimeter, within about 2 millimeters,within about 3 millimeters, within about 4 millimeters or within aboutfive millimeters of Müller's muscle.

In certain embodiments, the delivery system of the controlled-releasecomposition comprises PLGA microparticles. PLGA is a biocompatible,biodegradable polymer which can be used to encapsulate compounds forsustained-release administration. In some embodiments, the lacticacid-glycolic acid copolymer is a PLGA-PEG-PLGA triblock copolymer.Methods for preparing PLGA microparticles and encapsulating compoundswithin the microparticles are well known in the art (e.g., M. H. Lee etal., Biomaterials Research (2009) 13(1):11-15).

In general, water soluble forms of an alpha-adrenergic agent will elutefrom a delivery system faster than less water soluble forms of the samedrug. In certain embodiments, the disclosure provides compositions thatallow for modulation of the rate of local delivery in vivo of analpha-adrenergic agent from a delivery system. In particular, the rateof local delivery may be modulated by controlling the relativeproportion of a more slowly eluting form of an alpha-adrenergic agent toa more rapidly eluting form of an alpha-adrenergic agent. Control of thewater solubility of the agent to be delivered may be achieved in anumber of ways such as by using a salt or non-salt form of analpha-adrenergic agent. To control the release kinetics ofalpha-adrenergic agent from a delivery system, two or more forms of analpha-adrenergic agent with different solubilities may be combined in aproportion selected to achieve the desired kinetic profile.

To increase the water solubility of an alpha-adrenergic agent, the agentmay be converted from a neutral or non-salt form to a salt form. Thesalt form of an alpha-adrenergic agent will likely be more water solublethan the non-salt or neutral form of the same alpha-adrenergic gent.Generally, the soluble salt form of the alpha-adrenergic agent willelute from the delivery system of the disclosure at a faster rate than aneutral form of the alpha-adrenergic agent. By controlling the relativeproportions of the salt and non-salt forms of the alpha-adrenergic agentin the delivery systems of the disclosure, the rate and duration of drugdelivery from the delivery system may be controlled.

In addition to the idea of controlling release through the combinationof a salt and non-salt form of an alpha-adrenergic agent, the solubilityof an alpha-adrenergic agent may also be modulated through the choice ofa counterion for the salt form of the alpha-adrenergic agent.Counterions with greater hydrophilicity will generally increase elutionrate while more hydrophobic counterions will reduce elution rate. Forexample, an alkali metal counterion would likely confer greater watersolubility and faster elution rate than quaternary ammonium counterions.

In certain embodiments, the delivery systems of the disclosure, such aspolymer-based implants, have properties that help delay elution of thenon-salt form of an alpha-adrenergic agent from the delivery system.Generally, the non-salt form of the alpha-adrenergic agent will havestronger intermolecular attraction to the polymer material of a deliverysystem and thereby slow the elution rate of the non-salt form of thealpha-adrenergic agent from the delivery system.

In certain embodiments, the controlled release composition of thedisclosure comprises a delivery system, a first alpha-adrenergic agentin a free base or acid form and a second alpha-adrenergic agent in asalt form. In certain embodiments, the first alpha-adrenergic agent isan alpha-adrenergic agonist. In certain embodiments, the secondalpha-adrenergic agent is an alpha-adrenergic agonist. In certainembodiments, the first alpha-adrenergic agent is the non-salt form,e.g., free base or acid, of the second alpha-adrenergic agent. Forexample, the first alpha-adrenergic agent is oxymetazoline and thesecond alpha-adrenergic agent is a salt of oxymetazoline. Alternatively,the second alpha-adrenergic agent may be a salt of a differentalpha-adrenergic agent than the first alpha-adrenergic agent. Forexample, the first alpha-adrenergic agent may be oxymetazoline and thesecond alpha-adrenergic agent may be a salt of phenylephrine.

In certain embodiments, the compositions comprise a firstalpha-adrenergic agent in a non-salt form and a second alpha adrenergicagent in a salt form in a weight ratio of about 95:5 to about 30:70,such as about 95:5 to about 50:50, such as about 95:5 to about 60:40.

Other ways to control elution rate of an alpha-adrenergic agent from adelivery system include, for example, using a biodegradable deliverysystem that releases the alpha-adrenergic agent as it degrades in vivo,using an inclusion complex in the composition, using a solubilizingagent in the composition, and selecting a crystalline or amorphous formof an alpha-adrenergic agent for the composition.

A. Polymer-Based Implants

In some embodiments, the polymer-based implant is solid polymericimplant. In certain embodiments, the polymer-based implant is a liquidor semi-solid that solidifies in-situ, e.g., upon injection into tissue,thereby forming the implant. Polymer-based implants may be implantedinto the eyelid or surrounding area by surgical implantation or byinjection.

In certain embodiments, the release of the alpha-adrenergic agent issustained over a prescribed amount of time after implantation of thepolymer-based implant. In various embodiments, the release of thealpha-adrenergic agent is sustained for up to one day, up to two days,up to three days, up to four days, up to five days, up to six days, upto seven days, up to one week, up to two weeks, up to three weeks, up tofour weeks, up to one month, up to two months, up to three months, up tofour months, up to five months, up to six months, up to seven months, upto eight months, up to nine months, up to ten months, up to elevenmonths, up to twelve months, or up to one year after implantation.

In various embodiments, the implant comprises from about 0.1 mg to about10 mg of the alpha-adrenergic agent. In some embodiments, the implantcomprises about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about2.0 mg, 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg,about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg,3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, 4.1 mg,about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg,about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, 5.1 mg, about5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, 6.1 mg, about 6.2 mg,about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg,about 6.8 mg, about 6.9 mg, about 7.0 mg, 7.1 mg, about 7.2 mg, about7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about7.8 mg, about 7.9 mg, about 8.0 mg, 8.1 mg, about 8.2 mg, about 8.3 mg,about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg,about 8.9 mg, about 9.0 mg, 9.1 mg, about 9.2 mg, about 9.3 mg, about9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about9.9 mg, about 10 mg of the alpha-adrenergic agent. In certainembodiments, any two of the doses in this paragraph may be combined toform a range of dosages included within the disclosure, e.g., theimplant comprises from about 1.0 mg to about 8.0 mg of analpha-adrenergic agent.

In some embodiments, the implant comprises from about 0.1 mg to about 10mg of the alpha-adrenergic agent. In some embodiments, the implantcomprises from about 0.5 mg to about 8 mg of the alpha-adrenergic agent.In some embodiments, the implant comprises from about 2 mg to about 5 mgof the alpha-adrenergic agent. In some embodiments, the implantcomprises from about 3 mg to about 5 mg of the alpha-adrenergic agent.

In some embodiments, the implant comprises about 10 mg or less of thealpha-adrenergic agent. In some embodiments, the implant comprises about8 mg or less of the alpha-adrenergic agent. In some embodiments, theimplant comprises about 6 mg or less of the alpha-adrenergic agent. Insome embodiments, the implant comprises about 4 mg or less of thealpha-adrenergic agent.

In some embodiments, the implant comprises at least about 1 mg of thealpha-adrenergic agent. In some embodiments, the implant comprises atleast about 2 mg of the alpha-adrenergic agent. In some embodiments, theimplant comprises at least about 3 mg of the alpha-adrenergic agent. Insome embodiments, the implant comprises at least about 4 mg of thealpha-adrenergic agent.

1. Solid Polymeric Implants

In certain embodiments, a solid polymer-based implant is used toadminister the alpha-adrenergic agent. In some embodiments, the solidpolymer-based implant in surgically implanted into the eyelid, such asimplanted into the eyelid in close proximity to Müller's muscle. In someembodiments, the polymer-based implant comprises an alpha-adrenergicagent.

In various embodiments, the polymer of the polymer-based implant isselected from any polymer suitable for implantation into an animal. Incertain embodiments, the polymer-based implant comprises a biodegradablepolymer. “Biodegradable” is used to refer to any substance or objectthat can be decomposed by bacteria or another living organism. In someembodiments, the polymer is a biocompatible polymer. The terms“biocompatible polymer” and “biocompatibility” when used in relation topolymers are art-recognized. For example, biocompatible polymers includepolymers that are neither themselves toxic to the host (e.g., a cell, ananimal, or a human), nor degrade (if the polymer degrades) at a ratethat produces monomeric or oligomeric subunits or other byproducts attoxic concentrations in the host.

In certain embodiments, toxicology of a biodegradable polymer intendedfor intracellular or in vivo use, such as implantation or injection intoa patient, may be determined after one or more toxicity analyses. It isnot necessary that any subject composition have a purity of 100% to bedeemed biocompatible. Hence, a subject composition may comprise 99%,98%, 97%, 96%, 95%, 90% 85%, 80%, 75% or even less of biocompatiblepolymers, e.g., including polymers and other materials and excipientsdescribed herein, and still be biocompatible. Exemplary polymers thatmay be used in the polymer-based implants include: poly(caprolactone)(PCL), ethylene vinyl acetate polymer (EVA), poly(lactic acid) (PLA),poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(lacticacid-co-glycolic acid) (PLGA), poly(L-lactic acid-co-glycolic acid)(PLLGA), poly(D,L-lactide) (PDLA), poly(L-lactide) (PLLA),poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-caprolactone-co-glycolide),poly(D,L-lactide-co-PEO-co-D,L-lactide),poly(D,L-lactide-co-PPO-co-D,L-lactide), polyalkyl cyanoacralate,polyurethane, poly-L-lysine (PLL), hydroxypropyl methacrylate (HPMA),polyethyleneglycol, poly-L-glutamic acid, poly(hydroxy acids),polyanhydrides, polyorthoesters, poly(ester amides), polyamides,poly(ester ethers), polycarbonates, silicones, polyalkylenes such aspolyethylene, polypropylene, and polytetrafluoroethylene, polyalkyleneglycols such as poly(ethylene glycol) (PEG), polyalkylene oxides (PEO),polyalkylene terephthalates such as poly(ethylene terephthalate),polyvinyl alcohols (PVA), polyvinyl ethers, polyvinyl esters such aspoly(vinyl acetate), polyvinyl halides such as poly(vinyl chloride)(PVC), polyvinylpyrrolidone, polysiloxanes, polystyrene (PS),polyurethanes, derivatized celluloses such as alkyl celluloses,hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocelluloses, hydroxypropylcellulose, carboxymethylcellulose, polymers ofacrylic acids, such as poly(methyl(meth)acrylate) (PMMA),poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate),poly(isobutyl(meth)acrylate), poly(hexyl(meth)acrylate),poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate),poly(phenyl(meth)acrylate), poly(methyl acrylate), poly(isopropylacrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) (jointlyreferred to herein as “polyacrylic acids”), and copolymers and mixturesthereof, polydioxanone and its copolymers, polyhydroxyalkanoates,poly(propylene fumarate), polyoxymethylene, poloxamers,poly(ortho)esters, poly(butyric acid), poly(valeric acid),poly(lactide-co-caprolactone), trimethylene carbonate,polyvinylpyrrolidone, polyalkyl cyanoacrylate, polyethylenimine,dioleyltrimethyammoniumpropane/dioleyl-sn-glycerolphosphoethanolamine,poly sebacic anhydrides, polyurethane, nylons, or copolymers thereof,and the polymers described in Shieh et al., 1994, J. Biomed. Mater.Res., 28, 1465-1475, and in U.S. Pat. No. 4,757,128, Hubbell et al.,U.S. Pat. Nos. 5,654,381; 5,627,233; 5,628,863; 5,567,440; and5,567,435. Other suitable polymers include polyorthoesters (e.g. asdisclosed in Heller et al., 2000, Eur. J. Pharm. Biopharn., 50:121-128),polyphosphazenes (e.g. as disclosed in Vandorpe et al., 1997,Biomaterials, 18:1147-1152), and polyphosphoesters (e.g. as disclosed inEncyclopedia of Controlled Drug Delivery, pp. 45-60, Ed. E. Mathiowitz,John Wiley & Sons, Inc. New York, 1999), as well as blends and/or blockcopolymers of two or more such polymers. The carboxyl termini oflactide- and glycolide-containing polymers may optionally be capped,e.g., by esterification, and the hydroxyl termini may optionally becapped, e.g., by etherification or esterification. In certainembodiments, the polymer comprises or consists essentially of polyvinylchloride (PVC), polymethyl methacrylate (PMMA) and decyl methacrylate orcopolymers or any combination thereof. In polymers including lactic acidmonomers, the lactic acid may be D-, L-, or any mixture of D- andL-isomers.

The polymer of the polymer-based implant may comprise a plasticizer,such as dioctyl sebacate (DOS), o-nitrophenyl-octylether, dimethylphthalate, dioctylphenyl-phosphonate, dibutyl phthalate,hexamethylphosphoramide, dibutyl adipate, dioctyl phthalate, diundecylphthalate, dioctyl adipate, dioctyl sebacate, or other suitableplasticizers. In certain embodiments, the plasticizer is poly(glycerolsebacate) (PGS). In certain embodiments, the plasticizer includes thosedisclosed in U.S. Pat. Nos. 2,784,127 and 4,444,933.

2. Injectable Polymeric Implants

Injectable polymeric implants of the disclosure refer to a liquidpolymeric delivery system that can be injected into the eyelid where itforms a solid or semi-solid implant that releases the alpha-adrenergicagent in a controlled manner. In certain embodiments, the solid orsemi-solid implant formed from the liquid polymeric delivery system isbiodegradable. In certain embodiments, the liquid polymeric system isselected from thermoplastic polymers dissolved in a biocompatiblesolvent and thermosetting polymers that are liquids without the use ofsolvents. Thermosetting and thermoplastic formulations incorporate theadvantages of an implant while circumventing the need for surgery forimplantation of the implant.

a. Thermoplastic System

In certain embodiments, the liquid polymeric delivery system is athermoplastic system. A thermoplastic system may be obtained when asolid, linear-chain, polymer is dissolved in a biocompatible solvent toform a liquid, which can then be combined with the alpha-adrenergicagent and administered via a syringe. In certain embodiments, thethermoplastic system is prepared from a formulation with one or morepolymers. In certain embodiments, the polymer comprises a biodegradablepolymer. Examples of biodegradable polymers which can be used in thisapplication are polylactides, polyglycolides, polycaprolactones,polyanhydrides, polyamides, polyurethanes, polyesteramides,polyorthoesters, polydioxanones, polyacetals, polyketals,polycarbonates, polyorthocarbonates, polyphosphazenes,polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,polyalkylene succinates, poly(malic acid), poly(amino acids),polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin,chitosan, and copolymers, terpolymers, or combinations or mixtures ofthe above materials. In some embodiments, the polymers have a lowerdegree of crystallization and are more hydrophobic. These polymers andcopolymers may be more soluble in the biocompatible solvents than thehighly crystalline polymers such as polyglycolide and chitin which alsohave a high degree of hydrogen-bonding. In some embodiments, the polymeris a polyactide, apolycaprolactone, and copolymers of these withglycolide in which there are more amorphous regions to enhancesolubility.

In some embodiments, the solvent for the polymer is non-toxic, watermiscible, and otherwise biocompatible. The solvents must also bebiocompatible so that they do not cause severe tissue irritation ornecrosis at the site of implantation. Furthermore, the solvent should bewater miscible so that it will diffuse quickly into the body fluids andallow water to permeate into the polymer solution and cause it tocoagulate or solidify. Examples of such solvents include, but are notlimited to, N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propyleneglycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone,dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam,decylmethylsulfoxide, oleic acid, and 1-dodecylazacycloheptan-2-one. Insome embodiments, the solvent is N-methyl-2-pyrrolidone, 2-pyrrolidone,dimethyl sulfoxide, or acetone because of their solvating ability andtheir compatibility.

The solubility of the polymers in the various solvents will differdepending upon their crystallinity, their hydrophilicity,hydrogen-bonding, and molecular weight. Thus, not all of the polymerswill be soluble in the same solvent, but each polymer or copolymershould have its optimum solvent. Lower molecular-weight polymers maydissolve more readily in the solvents than high-molecular-weightpolymers. As a result, the concentration of a polymer dissolved in thevarious solvents will differ depending upon type of polymer and itsmolecular weight. Conversely, the higher molecular-weight polymers maytend to coagulate or solidify faster than the very low-molecular-weightpolymers. Moreover the higher molecular-weight polymers will tend togive higher solution viscosities than the low-molecular-weightmaterials. Thus for optimum injection efficiency, the molecular weightand the concentration of the polymer in the solvent should becontrolled.

For example, low-molecular-weight polylactic acid formed by thecondensation of lactic acid will dissolve in N-methyl-2-pyrrolidone(NMP) to give a 73% by weight solution which still flows easily througha 23-gauge syringe needle, whereas a higher molecular-weightpoly(DL-lactide) (DL-PLA) formed by the additional polymerization ofDL-lactide gives the same solution viscosity when dissolved in NMP atonly 50% by weight. The higher molecular-weight polymer solutioncoagulates immediately when placed into water. The low-molecular-weightpolymer solution, although more concentrated, tends to coagulate veryslowly when placed into water.

For polymers that tend to coagulate slowly, a solvent mixture can beused to increase the coagulation rate. For example, one liquid componentof the mixture may be a good solvent for the polymer, and the othercomponent is a poorer solvent or a non-solvent. The two liquids may bemixed at a ratio such that the polymer is still soluble but precipitateswith the slightest increase in the amount of non-solvent, such as waterin a physiological environment. By necessity, the solvent system must bemiscible with both the polymer and water. An example of such a binarysolvent system is the use of NMP and ethanol for low-molecular-weightDL-PLA. The addition of ethanol to the NMP/polymer solution increasesits coagulation rate significantly.

It has also been found that solutions containing very highconcentrations of high-molecular-weight polymers sometimes coagulate orsolidify slower than more dilute solutions. It is suspected that thehigh concentration of polymer impedes the diffusion of solvent fromwithin the polymer matrix and consequently prevents the permeation ofwater into the matrix where it can precipitate the polymer chains.

In some embodiments, the polymer comprises a block copolymer. In someembodiments, the block copolymer comprises hydrophilic poly(ethyleneoxide) blocks and a hydrophobic poly(propylene oxide) blocks. In someembodiments, the block copolymer is a triblock of poly(ethyleneoxide)-poly(propylene oxide)-poly(ethylene oxide) (marketed under thePluronic™ or Poloxamer™ tradenames). In some embodiments, this triblockcopolymer is dissolved in an aqueous solution. In some embodiments, thetriblock copolymer absorbs water to form a gel. In some embodiments, theblock copolymers are surface-active block copolymers which exhibitreverse thermal gelation behavior and possess drug-releasecharacteristics.

The Pluronic™, Poloxamer™ type triblock copolymers undergosolidification or gelation as the temperature of the solution is raisedabove a critical temperature (gelation temperature). These polymers formmicelles (microscopic spheres incorporating water) at low concentrationand turn into thick, continuous gels at high concentrations and elevatedtemperature (˜30° C.).

In some embodiments, the polymer comprises a lactic acid-glycolic acidcopolymer. In some embodiments, the lactic acid-glycolic acid copolymeris a PLGA-PEG-PLGA triblock copolymer. Suitable PLGA-PEG-PLGA triblockcopolymers are commercially available from PolySciTech (a Division ofAkina, Inc.) of West Lafayette, Ind. Thermo-sensitive PLGA-PEG-PLGAtriblock copolymers are well described in the art. These polymers mayhave molecular weights from about 2000 Da to about 40,000 Da, but mayhave any molecular weight provided that it has the required reversethermo-sensitive properties. In some embodiments, the PLGA-PEG-PLGAtriblock polymers may have a molecular weight of about 30,000 Da. Insome other embodiments, the PLGA-PEG-PLGA triblock polymers may have amolecular weight of about 4000 Da. In some other embodiments, thePLGA-PEG-PLGA triblock copolymer may have a molecular weightdistribution of 1500:1000:1500 but as one of ordinary skill in the artshould appreciate, other molecular weight distributions may be possibleand are within the scope of the present disclosure. The ratio of lacticacid to glycolic acid in the PLGA segments of the polymer may not becritical provided that the polymer has the required thermo-sensitiveproperties. In some embodiments, the PLGA segment of the copolymer has alactic acid to glycolic acid ratio of about 1:1 and in some otherembodiments, the PLGA segment of the copolymer has a lactic acid toglycolic acid ratio of about 3:1.

In some embodiments, the alpha-adrenergic agent described herein isadded to the polymer solution prior to injection, and then thepolymer/solvent/agent mixture is injected into the eyelid. In someembodiments, the formulation is injected intradermally, subcutaneously,pre-septally, post-septally, into the post septal fat pad, orintramuscularly. In some cases, the alpha-adrenergic agent is soluble inthe solvent, and a homogenous solution of polymer and alpha-adrenergicagent may be used for injection. In other cases, the alpha-adrenergicagent is not soluble in the solvent, and a suspension or dispersion ofthe agent will result. In some embodiments, the suspension or dispersionis injected into the eyelid. In certain embodiments, upon injection, thesolvent will dissipate and the polymer will solidify and entrap orencase the alpha-adrenergic agent within a solid or semi-solid matrix.The release of agent from these solid or semi-solid in-situ formingimplants may follow the same general rules for release of a agent from amonolithic polymeric device. The release of drug may be affected by thesize and shape of the implant, the loading of drug within the implant,the permeability factors involving the drug and the particular polymer,and the degradation of the polymer.

The amount of alpha-adrenergic agent incorporated into the injectable,in-situ, solid forming implant depends upon the desired release profile,the concentration of drug required for a biological effect, and thelength of time that the drug has to be released for treatment. The lowerlimit of the alpha-adrenergic agent incorporated into the deliverysystem is dependent upon the activity of alpha-adrenergic agent and thelength of time needed for treatment.

B. Thermosetting System

In certain embodiments, the liquid polymeric delivery system is athermosetting system. In certain embodiment, the thermosetting systemcomprises one or more biocompatible polymers. In some embodiments, thethermosetting system comprises crosslinkable polymers which can beformed and cured in-situ through the use of a curing agent. The polymersmay be first formed using a polyol initiator and catalyst to formpolyol-terminated prepolymers which are further converted to acrylicester-terminated prepolymers. Just prior to injection, a curing agentsuch as benzoyl peroxide or azobisisobutyronitrile is added to theacrylic prepolymer solution. Once injected, the crosslinking reactionproceeds until sufficient molecular weight has been obtained to causethe polymer to solidify. In some embodiments, the curing reaction israpid and injection must take place almost immediately following theaddition of the curing agent. These polymers may be formed primarily bythe polymerization or copolymerization of biodegradable hydrophobicpolylactides, polyglycolides, polycaprolactones and the like. In someembodiments, the biodegradable system comprises a bifunctional polyestersynthesized from a bifunctional chain initiator such as ethylene glycol.In some embodiments, the biodegradable system comprises a trifunctionalpolyester synthesized from a trifunctional initiator such astrimethylolpropane. The amount of chain initiator may determine theresultant molecular weight of the polymer or copolymer. In certainembodiments, the gel matrix once formed will release the agent in acontrolled manner and degrade to products which are easily metabolizedand excreted.

In some embodiments, the solid implant formed within the injectablepolymer solution will slowly biodegrade within the body and allownatural tissue to grow and replace the implant as it disappears. In someembodiments, the solid implant formed from the injectable system willrelease the alpha-adrenergic agent contained within its matrix at acontrolled rate until the drug is depleted. In some embodiments, thepolymer will degrade after the drug has been completely released. Insome other embodiments, the drug will be completely released only afterthe polymer has degraded to a point where the non-diffusing drug hasbeen exposed to the body fluids.

In various embodiments, the choice of polymer dictates the rate ofrelease of the alpha-adrenergic agent.

Microneedles

In some embodiments, the alpha-adrenergic agent is packaged in or onmicroneedles. Microneedles are structures of typically micrometer tomillimeter size, and designed to pierce the skin and deliver acomposition to the epidermis or dermis of a subject. In someembodiments, the skin pierced by the microneedles is or is around theeyelid. Microneedles offer some advantages over traditionalsub-cutaneous or intramuscular injections. First, the amount ofalpha-adrenergic agent needed for administration can be smaller, cuttingdown on production cost and time. Second, the microneedle can beself-administered. Third, the alpha-adrenergic agent can be dried ontothe microneedle, which greatly increases the stability of thecomposition at room temperatures. Moreover, microneedle administrationis typically painless which may make it a more tolerated form ofadministration.

Microneedles are typically solid or hollow structures. When used as asolid support, the alpha-adrenergic agent for delivery can coat themicroneedle (typically as a dried form) or can be released throughhollow structures (e.g. liquid composition is injected or infused intothe skin). Compositions can be on microneedles (for example, coated ontoa surface of the microneedles after formation), or in microneedles (forexample, forming part of the microneedle itself, such as by depositioninto the interior of the microneedle, or by inclusion in a mixture usedto form the microneedles). In some embodiments, the alpha-adrenergicagent is dissolved in the skin compartment or is injected into the skin.Microneedles are often formed in arrays, comprising multiple needle-likestructures, such as on a patch. In some embodiments, the microneedlearray is then applied directly to the skin for intradermaladministration of a composition.

In some embodiments, the microneedle array patch is designed to be anyshape or size. For example, a microneedle array patch for delivery ofthe alpha-adrenergic agent for cosmetic purposes can be shaped to mimicfacial features, e.g., eyelids. In some embodiments, the microneedlearray patch is of any size, but will preferably be the smallest sizeallowable to deliver a selected amount of the alpha-adrenergic agent.

The size and shape of the microneedles may also vary as desired. In someembodiments, the microneedles include a cylindrical portion upon whichis positioned a conical portion having a tip. In some other embodiments,the microneedles have an overall pyramidal shape, or an overall conicalshape. In general, the microneedle typically includes a base and a tip.In some embodiments, the tip has a radius that is less than or equal toabout 1 micrometer. The microneedles are typically of a lengthsufficient to penetrate the stratum corneum and pass into the epidermisor dermis. In certain embodiments, the microneedles have a length (fromtheir tip to their base) from about 0.1 micrometer to about 5millimeters in length, for instance about 5 millimeters or less, 4millimeters or less, from about 1 millimeter to about 4 millimeters,from about 500 micrometers to about 1 millimeter, from about 10micrometers to about 500 micrometers, from about 30 micrometers to about200 micrometers, or from about 250 micrometers to about 1500micrometers.

In some embodiments, the size of individual microneedles is optimizeddepending upon the desired targeting depth, the strength requirements ofthe needle to avoid breakage in a particular tissue type, etc. In someembodiments, the cross-sectional dimension of a transdermal microneedleis from about 10 nm to about 1 mm, or from about 1 micrometers to about200 micrometers, or from about 10 micrometers to about 100 micrometers.The outer diameter may be from about 10 micrometers to about 100micrometers and the inner diameter of a hollow needle may be from about3 micrometers to about 80 micrometers.

In some embodiments, the microneedles are arranged on a substrate in avariety of patterns, and such patterns are designed for a particularuse. In some embodiments, the microneedles are spaced apart in a uniformmanner, such as in a rectangular or square grid or in concentriccircles. The spacing may depend on numerous factors, including heightand width of the microneedles, the characteristics of a film to beapplied to the surface of the microneedles, as well as the amount andtype of a substance that is intended to be moved through themicroneedles. An example arrangement of microneedles is a “tip-to-tip”spacing between microneedles of about 50 micrometers or more, in someembodiments about 100 to about 800 micrometers, and in some embodiments,from about 200 to about 600 micrometers.

In some embodiments, the microneedle composition is of any suitablematerial. Example materials include metals, ceramics, semiconductors,organics, polymers, and composites. In some embodiments, materials ofconstruction include pharmaceutical grade stainless steel, gold,titanium, nickel, iron, gold, tin, chromium, copper, alloys of these orother metals, silicon, silicon dioxide, and polymers. Representativebiodegradable polymers include polymers of hydroxy acids such as lacticacid and glycolic acid polylactide, polyglycolide,polylactide-co-glycolide, and copolymers with PEG, polyanhydrides,poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valericacid), and poly(lactide-co-caprolactone). Representativenon-biodegradable polymers include polycarbonate, polymethacrylic acid,ethylenevinyl acetate, polytetrafluorethylene and polyesters. In someembodiments, the microneedle is dissolvable, biosoluble, orbiodegradable, or a combination thereof. A variety of dissolvable and/orbiosoluble microneedles may be used. (see e.g., US20140200509, andWO2009021048 which are herein incorporated by reference in theirentireties). Briefly, dissolvable microneedles may be composed of watersoluble materials. These materials can include, by way of example,chitosan, collagen, gelatin, maltose, dextrose, galactose, alginate,agarose, cellulose such as carboxymethylcellulose orhydroxypropylcellulose, starch, and hyaluronic acid. In general, aselected material will be resilient enough to allow for penetration ofthe skin. Preferably, the dissolvable microneedle will dissolve in theskin within seconds, such as within about 5, 10, 15, 20, 25, 30, 45, 50,60, 120, 180, or more seconds; or within minutes, such as within about1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 60, 120 or more minutes. Thedissolvable microneedle can encompass the entire microneedle, such thatthe entire microneedle structure will dissolve in the skin, or adissolvable coating can be formed on a non-dissolvable support structuresuch that only the coating will dissolve in the skin. The microneedlemay be coated with a polymer that is dissolvable, biodegradable,biosoluble, or a combination thereof.

In some embodiments, the alpha-adrenergic agent compositions are coatedon the dissolvable microneedle or are contained within the dissolvablemicroneedle itself (e.g. by forming part of the dissolvable polymermatrix). In some embodiments, the alpha-adrenergic agent composition isdirectly coated onto microneedle structures, or is mixed with a polymermatrix prior to molding and polymerization of microneedle structures.

For examples of biodegradable microneedles, see e.g., WO200801068 andU.S. Pat. No. 6,334,856, each of which are hereby incorporated byreference.

A variety of suitable methods for making microneedles are available (seee.g. U.S. Pat. Nos. 6,312,612, 6,334,856, 7,182,747, 7,226,439, andWO2013137831). In some embodiments, the microneedles are manufacturedusing a variety of methods including, but not limited to, molding (e.g.,self-molding, micromolding, microembossing, microinjection and thelike), casting (e.g., die-casting), etching (e.g. soft microlithographytechniques), and the like. The method of manufacture used will typicallydepend on the materials employed.

In some embodiments, the microneedle composition comprises one or morealpha-adrenergic agents.

In various embodiments, the release of the alpha-adrenergic agent issustained over a prescribed amount of time. In various embodiments, therelease of the alpha-adrenergic agent is sustained over a period of 4hours or more. In various embodiments, the release of thealpha-adrenergic agent is sustained over a period of 8 hours or more. Invarious embodiments, the release of the alpha-adrenergic agent issustained over a period of 12 hours or more. In various embodiments, therelease of the alpha-adrenergic agent is sustained for up to one day, upto two days, up to three days, up to four days, up to five days, up tosix days, up to seven days, up to one week, up to two weeks, up to threeweeks, up to four weeks, up to one month, or up to two months.

In various embodiments, the microneedle array comprises from about 0.1mg to about 10 mg of the alpha-adrenergic agent. In some embodiments,the microneedle array comprises about 0.1 mg, about 0.2 mg, about 0.3mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8mg, about 1.9 mg, about 2.0 mg, 2.1 mg, about 2.2 mg, about 2.3 mg,about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg,about 2.9 mg, about 3.0 mg, 3.1 mg, about 3.2 mg, about 3.3 mg, about3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about3.9 mg, about 4.0 mg, 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg,about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg,about 5.0 mg, 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about6.0 mg, 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg,about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg,7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, 8.1 mg,about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg,about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, 9.1 mg, about9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about9.7 mg, about 9.8 mg, about 9.9 mg, about 10 mg of the alpha-adrenergicagent. In certain embodiments, any two of the doses in this paragraphmay be combined to form a range of dosages included within thedisclosure, e.g., the microneedle array comprises from about 1.0 mg toabout 8.0 mg of an alpha-adrenergic agent.

In some embodiments, the microneedle array comprises from about 0.1 mgto about 10 mg of the alpha-adrenergic agent. In some embodiments, themicroneedle array comprises from about 0.5 mg to about 8 mg of thealpha-adrenergic agent. In some embodiments, the microneedle arraycomprises from about 2 mg to about 5 mg of the alpha-adrenergic agent.In some embodiments, the microneedle array comprises from about 3 mg toabout 5 mg of the alpha-adrenergic agent.

In some embodiments, the microneedle array comprises about 10 mg or lessof the alpha-adrenergic agent. In some embodiments, the microneedlearray comprises about 8 mg or less of the alpha-adrenergic agent. Insome embodiments, the microneedle array comprises about 6 mg or less ofthe alpha-adrenergic agent. In some embodiments, the microneedle arraycomprises about 4 mg or less of the alpha-adrenergic agent.

In some embodiments, the microneedle array comprises at least about 1 mgof the alpha-adrenergic agent. In some embodiments, the microneedlearray comprises at least about 2 mg of the alpha-adrenergic agent. Insome embodiments, the microneedle array comprises at least about 3 mg ofthe alpha-adrenergic agent. In some embodiments, the microneedle arraycomprises at least about 4 mg of the alpha-adrenergic agent.

Methods of Use

In certain aspects, any of the compositions described herein may be usedin the treatment of ptosis, for cosmetic alteration of the eyelid, orother related uses. The compositions of the disclosure are preferablyapplied topically on the eye or eyelid, are injected into the eyelid, orare released from implants in the eyelid or inserts near the eyelid. Incertain embodiments, a controlled-release composition of the disclosureis used for the treatment of ptosis or cosmetic alteration of the eyelidor other related uses. The compositions used in the methods describedherein may be selected from any of parenteral compositions, topicalcompositions, controlled-release compositions, microneedles, transdermalformulations and any other compositions described herein. In certainembodiment, the alpha-adrenergic agent of the methods described hereinis an alpha-adrenergic agonist such as oxymetazoline or a salt thereof.

As used herein, the terms “treatment” or “treating” are usedinterchangeably herein. These terms refer to an approach for obtainingbeneficial or desired results including but not limited to a therapeuticbenefit, cosmetic benefit and/or a prophylactic benefit. A therapeuticbenefit can mean eradication or amelioration of the underlying disorderbeing treated. Also, a therapeutic benefit can be achieved with theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that an improvement isobserved in the subject, notwithstanding that the subject may still beafflicted with the underlying disorder. A prophylactic effect includesdelaying or eliminating the appearance of a disease or condition,delaying or eliminating the onset of symptoms of a disease or condition,slowing, halting, or reversing the progression of a disease orcondition, or any combination thereof. For prophylactic benefit, thecompositions may be administered to a subject at risk of developing aparticular disease, or to a subject reporting one or more of thephysiological symptoms of a disease, even though a diagnosis of thisdisease may not have been made. A cosmetic benefit may mean affecting aphysical change to a subject that is desired by the subject.

As used herein, the term “effective amount” or “therapeuticallyeffective amount” refers to the amount of a compound that is sufficientto affect the intended application, including but not limited tocosmetic treatment and disease treatment, as defined below. Thetherapeutically effective amount may vary depending upon the intendedtreatment application (in vivo), or the subject and disease conditionbeing treated, e.g., the severity of the disease condition, the mannerof administration and the like, which can readily be determined by oneof ordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells. The specific dose willvary depending on the particular compounds chosen, the dosing regimen tobe followed, whether it is administered in combination with othercompounds, timing of administration, the tissue to which it isadministered, and the physical delivery system in which it is carried.

In certain aspects, the disclosure provides a method for treating ptosisin a subject, comprising administering an effective amount of analpha-adrenergic agent into the eyelid of the subject, such asadministration through injection into the eyelid. In certainembodiments, the injection is administered intradermally,subcutaneously, pre-septally, post-septally, into the post-septal fatpad, or intramuscularly. In particular embodiments, the injection isadministered intramuscularly into Müller's muscle or the levator muscleor both. In certain embodiments, the injection is administeredsubcutaneously, adjacent to Müller's muscle or the levator muscle.

In certain embodiments, the method for treating ptosis in a subjectcomprises administering a controlled-release composition into the eyelidof the subject. The controlled-release composition may be administeredinto the eyelid through surgical implantation or the controlled-releasecomposition may be administered into the eyelid through injection. Incertain embodiments, a controlled-release implant is injected into theeyelid of a subject. For example, a solid polymer-based implant may beinjected into the eyelid of the subject.

In certain embodiments, a controlled-release implant is formed uponinjection of an injectable polymeric composition, e.g., a thermosettingor thermoplastic composition. In certain such embodiments, theinjectable polymeric composition forms a solid or semi-solid implantonce injected into the tissue of the subject.

In certain embodiments, the disclosure provides a method of treatingptosis in a subject, comprising contacting one or more muscles in theeyelid with an effective amount of an alpha-adrenergic agent. In certainembodiments, the method of treating ptosis in a subject comprisescontacting any one or more of the superior tarsal muscle, the orbitalismuscle, and the levator palpebrae superioris muscle. In certainembodiments, the method comprises directly contacting a muscle in theeyelid by, for example, injecting an alpha-adrenergic composition intothe eyelid or implanting an alpha-adrenergic containing implant into theeyelid. The method may comprise indirectly contacting a muscle in theeyelid by, for example, applying a topical composition that permeatesthe skin of the eyelid. In certain such embodiments, the topicalcomposition may be a transdermal formulation.

In certain embodiments, the method of the disclosure comprisescontacting Müller's muscle and/or the levator muscles of the subjectwith an effective amount of an alpha-adrenergic agent. Müller's muscle,also referred to as the orbitalis muscle, is a smooth muscle thatcrosses from the infraorbital groove and sphenomaxillary fissure and isintimately united with the periosteum of the orbit. Müller's muscle liesat the back of the orbit and spans the infraorbital fissure.

In certain embodiments, contacting a muscle, such as Müller's muscle, ofthe subject occurs through parenteral administration of thealpha-adrenergic agent, such as through injection of thealpha-adrenergic agent into the eyelid of the subject. In certainembodiments, parenteral administration is injection of thealpha-adrenergic agent in an area on the face adjacent to the eyelid,such as injection into the angular vein.

In certain embodiments, the alpha-adrenergic agent is administered in acontrolled-release composition. In certain embodiments, contacting amuscle, such as Müller's muscle, of the subject occurs through releaseof an alpha-adrenergic agent from a controlled-release composition,e.g., such as a polymer-based implant described herein, implanted intothe eyelid of the subject. In certain embodiments, contacting a muscle,such as Müller's muscle, of the subject occurs through release of analpha-adrenergic agent from an insert positioned under the eyelid or incontact with the eyelid of the subject.

In certain aspects, the disclosure provides a method for treating ptosisin a subject, comprising administering a controlled-release compositioninto the eyelid, in contact with the eyelid, or in close proximity tothe eyelid of the subject, wherein the controlled-release compositionreleases a therapeutically effective amount of an alpha-adrenergic agentto the subject. In certain embodiments, the controlled-releasecomposition is selected from any of the controlled-release compositiondescribed herein. In particular embodiments, the method comprisesadministering a controlled-release composition as an implant in theeyelid of the subject. In particular embodiments, the implant isbiodegradable in vivo. In particular embodiments, the method comprisesadministering a controlled-release composition of an effective amount ofan alpha-adrenergic agent to the subject as an injectable polymericimplant. In particular embodiments, the alpha-adrenergic agent of themethod is oxymetazoline of a salt thereof.

In certain aspects, the disclosure provides a method for cosmetictreatment of a subject, comprising administering an effective amount ofan alpha-adrenergic agent into the eyelid of the subject, such asadministration through injection into the eyelid. In certainembodiments, the injection is administered intradermally,subcutaneously, pre-septally, post-septally, into the post-septal fatpad, or intramuscularly. In particular embodiments, the injection isadministered intramuscularly into Müller's muscle or the levator muscleor both. In certain embodiments, the injection is administeredsubcutaneously, adjacent to Müller's muscle or the levator muscle.

In certain embodiments, the method for cosmetic treatment of a subjectcomprises administering a controlled-release composition into the eyelidof the subject. The controlled-release composition may be administeredinto the eyelid through surgical implantation or the controlled-releasecomposition may be administered into the eyelid through injection. Incertain embodiments, a controlled-release implant is injected into theeyelid of a subject. For example, a solid polymer-based implant may beinjected into the eyelid of the subject.

In certain embodiments, a controlled-release implant of the cosmeticmethod is formed upon injection of an injectable polymeric composition,e.g., a thermosetting or thermoplastic composition. In certain suchembodiments, the injectable polymeric composition forms a solid orsemi-solid implant once injected into the tissue of the subject.

In certain embodiments, the disclosure provides a method of cosmetictherapy of a subject comprising contacting one or more muscles in theeyelid with an effective amount of an alpha-adrenergic agent. In certainembodiments, the method of cosmetic therapy of a subject comprisescontacting any one or more of the superior tarsal muscle, the orbitalismuscle, and the levator palpebrae superioris muscle. In certainembodiments, the method comprises directly contacting a muscle in theeyelid by, for example, injecting an alpha-adrenergic composition intothe eyelid or implanting an alpha-adrenergic containing implant into theeyelid. The method may comprise indirectly contacting a muscle in theeyelid by, for example, applying a topical composition that permeatesthe skin of the eyelid. In certain such embodiments, the topicalcomposition may be a transdermal formulation.

In certain embodiments, the method of cosmetic therapy comprisescontacting Müller's muscle and/or the levator muscles of the subjectwith an effective amount of an alpha-adrenergic agent. In certainembodiments, contacting a muscle, such as Müller's muscle, of thesubject occurs through parenteral administration of the alpha-adrenergicagent, such as through injection of the alpha-adrenergic agent into theeyelid of the subject. In certain embodiments, parenteral administrationis injection of the alpha-adrenergic agent in an area on the faceadjacent to the eyelid, such as injection into the angular vein.

In certain embodiments, the method of cosmetic therapy of a subjectcomprises administering an alpha-adrenergic agent in acontrolled-release composition. In certain embodiments, directcontacting a muscle such as Müller's muscle of the subject occursthrough release of an alpha-adrenergic agent from a controlled-releasecomposition, e.g., such as a polymer-based implant described herein,implanted into the eyelid of the subject. In certain embodiments,indirect contacting a muscle such as Müller's muscle of the subjectoccurs through release of an alpha-adrenergic agent from an insertpositioned under the eyelid or in contact with the eyelid of thesubject.

In certain aspects, the disclosure provides a method for cosmetictherapy of a subject, comprising administering a controlled-releasecomposition into the eyelid, in contact with the eyelid, or in closeproximity to the eyelid of the subject, wherein the controlled-releasecomposition releases a therapeutically effective amount of analpha-adrenergic agent to the subject. In certain embodiments, thecontrolled-release composition is selected from any of thecontrolled-release compositions described herein. In particularembodiments, the method of cosmetic therapy comprises administering acontrolled-release composition as an implant in the eyelid of thesubject. In particular embodiments, the implant is biodegradable invivo. In particular embodiments, the method comprises administering acontrolled-release composition of an effective amount of analpha-adrenergic agent to the subject as an injectable polymericimplant. In particular embodiments, the alpha-adrenergic agent of themethod is oxymetazoline of a salt thereof.

In certain embodiments, the controlled-release composition of thedisclosure provides sustained-release of the alpha-adrenergic agent overa period of two weeks or more, such as three weeks or more, such as fourweeks or more, such as five weeks of more, such as six weeks or more,such as seven weeks or more, such as eight weeks or more such as noneweeks or more, such as ten weeks or more, such as eleven weeks or more,such as twelve weeks or more, such as thirteen weeks or more, such asfourteen weeks or more, such as fifteen weeks or more, or even such assixteen weeks or more.

In certain embodiments, the controlled-release composition of thedisclosure provides sustained-release of the alpha-adrenergic agent overa period of about two weeks, about three weeks, about four weeks, aboutfive weeks, about six weeks, about seven weeks, about 8 weeks, aboutnine weeks, about ten weeks, about eleven weeks, about twelve weeks,about thirteen weeks, about fourteen weeks, about fifteen weeks, or evenabout sixteen weeks. In certain embodiments, the controlled-releasecomposition of the disclosure provides sustained-release of thealpha-adrenergic agent over a period of about one month, about twomonths, about three months, about four months, about five months, aboutsix months, about seven months, about eight months, about nine months,about ten months, about eleven months, or even about twelve months. Incertain embodiments, any two of the time frames in this paragraph may becombined to form a range of time frames included within the disclosure,e.g., the controlled-release composition of the disclosure providessustained-release of the alpha-adrenergic agent over a period of aboutthree weeks to about four months.

The term “controlled release”, as used herein, refers to release ofpredetermined amounts of an alpha-adrenergic agent into the body over aspecified time period. Controlled-release compositions includesustained-release compositions, delayed-release compositions,targeted-release drug products, etc. The term “sustained-release”, asused herein, refers to release of an alpha-adrenergic agent at apredetermined rate in order to maintain a constant or near-constant drugconcentration for a period of time.

In certain aspects, the disclosure provides a method for increasing thevertical separation of the upper and lower eyelids of a subject relativeto a pre-treatment separation, comprising administering an effectiveamount of an alpha-adrenergic agent to the eye or eyelid of a subject.In particular embodiments, the subject does not have ptosis. In certainembodiments, the alpha-adrenergic agent is administered as acontrolled-release composition. In certain embodiments, thealpha-adrenergic is administered topically to the eye or eyelid. Inparticular embodiments, the alpha-adrenergic agent is administered tothe eyelid of the subject, such as into the eyelid of a subject. Incertain embodiments, the vertical separation of the upper and lowereyelids is increased by 10 percent or more relative to the pre-treatmentseparation.

In certain embodiments, the methods of the disclosure increase thevertical separation of the upper and lower eyelid by about 1% or more,about 2% or more, about 3% or more, about 4% or more, about 5% or moreabout 6% or more, about 7% or more, about 8% or more, about 9% or more,about 10% or more, about 11% or more, about 12% or more, about 13% ormore, about 14% or more, about 15% or more, about 16% or more, about 17%or more about 18% or more, about 19% or more, about 20% or more, about21% or more, about 22% or more, about 23% or more, about 24% or more,about 25% or more, about 26% or more, about 27% or more, about 28% ormore about 29% or more, about 30% or more, about 31% or more, about 32%or more, about 33% or more, about 34% or more, about 35% or more, about36% or more, about 37% or more, about 38% or more about 39% or more,about 40% or more, about 41% or more, about 42% or more, about 43% ormore, about 44% or more, about 45% or more, about 46% or more, about 47%or more, about 48% or more about 49% or more, about 50% or more,relative to the pre-treatment vertical separation of the upper and lowereyelids.

In certain embodiments, the methods of the disclosure increase thedistance of the upper eyelid from the midpupil. Drooping eyelids orptotic eyelids may have a distance between the upper eyelid and themidpupil of about 2 mm or less. In certain embodiments, methods of thedisclosure increase the distance between the upper eyelid and midpupilto about 2 mm or more, about 2.1 mm or more, about 2.2 mm or more, about2.3 mm or more, about 2.4 mm or more, about 2.5 mm or more, about 2.6 mmor more, about 2.7 mm or more, about 2.8 mm or more, about 2.9 mm ormore, about 3.0 mm or more, about 3.1 mm or more, about 3.2 mm or more,about 3.3 mm or more, about 3.4 mm or more, about 3.5 mm or more, about3.6 mm or more, about 3.7 mm or more, about 3.8 mm or more, about 3.9 mmor more, or even about 4.0 mm or more, relative to the pre-treatmentdistance of the upper eyelid from the midpupil.

In certain embodiments, methods of the disclosure reduce the asymmetrybetween the two upper eyelids.

In certain embodiments, the disclosure provides a method of changing thelocation of the visual axis of a subject, comprising administering aneffective amount of an alpha-adrenergic agent to the eye or into theeyelid of the subject. In particular embodiments, the subject does nothave ptosis. In certain embodiments, the alpha-adrenergic agent isadministered as a controlled-release composition. In certainembodiments, the alpha-adrenergic is administered topically to the eyeor eyelid. In particular embodiments, the alpha-adrenergic agent isadministered to the eyelid of the subject, such as into the eyelid of asubject. In certain embodiment, changing the location of the visual axisimproves the subject's vision. Improving the subject's vision mayinclude any of: improving visual acuity, improving contrast sensitivity,reducing glare and halos, and increasing the amount of aperture throughwhich the subject has good vision.

Diagnostic Methods

In certain embodiments, the disclosure provides methods for screeningsubjects who would benefit from the methods disclosed herein, using analpha-adrenergic agent. In particular embodiments, an alpha-adrenergicagent is administered topically as a screening dose to the eye or eyelidof a subject to determine whether the eyelid of the subject responds tothe administration of the alpha-adrenergic agent. In certainembodiments, if the subject's eyelid responds to the topicaladministration of the alpha-adrenergic agent, the subject may beadministered a treatment regimen of an alpha-adrenergic agent in theform of a topical or parenteral administration. In particularembodiments, a subject is administered a topical alpha-adrenergic agentand if the eyelid responds to the administration, the subject isadministered one or more doses of alpha-adrenergic agent by injectioninto the eyelid, as described in the methods disclosed herein.

In certain embodiments, the “eyelid responds to the administration” byretracting, such that the vertical separation of the lower and uppereyelids of the eye treated increases. For example, a subject isadministered a topical alpha-adrenergic agent, e.g., oxymetazoline eyedrops in the eye, and the upper eyelid of said eye retracts upwardlysuch that the vertical separation of the lower and upper eyelidsincreases by about 0.5 mm or more, such as about 1 mm or more or evenabout 2 mm or more.

If the upper eyelid of the eye treated with an alpha-adrenergic agentresponds to the screening dose, any of the methods of use described inthe preceding section may be used on the subject. For example, if theupper eyelid of the subject's eye treated with an alpha-adrenergic agentresponds to the screening administration, the subject may receive aninjection of an alpha-adrenergic agent, the subject may apply a topicalcomposition of an alpha-adrenergic agent into the eye or on the eyelidor any combination thereof.

In certain embodiments, the screening method provides informationregarding suitable dosages or methods of administration ofalpha-adrenergic agents. For example, a subject's eyelid may not retractor retract minimally upon administration of a screening dosage of analpha-adrenergic agent. As used herein, “retract minimally” may refer toan increase in vertical separation of the upper and lower eyelids ofless than 2 mm such as from about 0.1 mm to about 2 mm, about 0.1 mm toabout 1.5 mm, about 0.1 mm to about 1 mm, about 0.1 to about 0.8 mm oreven about 0.1 to about 0.5 mm relative to the position of the eyelidsprior to administration of the alpha-adrenergic agent. When a subject'seyelid does not retract or retracts minimally upon administration of thetopical alpha-adrenergic agent screening dose, the subject may receive asecond screening dose that is higher than the first screening dose todetermine whether the subject's eyelid responds to the higher dose.

In certain embodiments, the response of the subject to the topicalscreening dose of the alpha-adrenergic agent may be used to determinethe dose or frequency of administration of an alpha-adrenergic agentadministered to the subject. For example, a subject's eyelid displays alarge retractive response upon administration of the topical screeningdose, and therefore the subject may be prescribed a low dose of analpha-adrenergic agent. Alternatively, a subject's eyelid may display asmall retractive response upon administration of the screening dose, andtherefore the subject may be prescribed a high dose of alpha-adrenergicagent.

In certain embodiments, the administration method of an alpha-adrenergicagent may be prescribed based upon the subject's response to thescreening dose. For example, a subject's eyelid displays a largeretractive response upon administration of the topical screening dose,and therefore the subject may be prescribed a topical treatment regimen.Alternatively, a subject's eyelid may display a small retractiveresponse upon administration of the screening dose, and therefore thesubject may be prescribed a parenteral treatment regimen either alone orin combination with a topical treatment regimen.

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

The invention is further described in detail by reference to thefollowing examples. These examples are provided for the purpose ofillustration only, and are not intended to be limiting unless otherwisespecified. Thus, the invention should in no way be construed as beinglimited to the following examples, but rather, should be construed toencompass any and all variations which become evident as a result of theteaching provided herein.

Embodiments contemplated herein include embodiments P1 to P48.

Embodiment P1. A controlled-release composition, comprising analpha-adrenergic agent and a delivery system which controls the releaseof the alpha-adrenergic agent.

Embodiment P2. The controlled-release composition of embodiment P1,wherein the composition is selected from a sustained-releasecomposition, a prolonged release composition, a pulsatile releasecomposition and a delayed-release composition.

Embodiment P3. The controlled-release composition of embodiment P1 orP2, wherein the delivery system is selected from polymer-based systems,porous matrices, hydrogel release systems, and peptide-based systems.

Embodiment P4. The controlled-release composition of any embodiments P1to P3, wherein the composition is a sustained-release composition.

Embodiment P5. The controlled-release composition of embodiment P4,wherein the sustained-release composition is formulated for injection.

Embodiment P6. The controlled-release composition of embodiment P6,wherein the composition is formulated for injection intradermally,subcutaneously, pre-septally, post-septally, into the post-septal fatpad, or intramuscularly.

Embodiment P7. The controlled-release composition of any one ofembodiments P1 to P6, wherein the composition comprises from 0.2 to 10mg of the alpha-adrenergic agent.

Embodiment P8. The controlled-release composition of embodiment P7,wherein the composition comprises from 0.5 to 8 mg of thealpha-adrenergic agent.

Embodiment P9. The controlled-release composition of embodiment P7,wherein the composition comprises 0.5 to 3 mg of the alpha-adrenergicagent.

Embodiment P10. The controlled-release composition of embodiment P7,wherein the composition comprises 3 to 6 mg of the alpha-adrenergicagent.

Embodiment P11. The controlled-release composition of embodiment P4,wherein the sustained-release composition is formulated for topicaladministration.

Embodiment P12. The controlled-release composition of embodiment P1,wherein the composition is formulated for administration to the eyelid.

Embodiment P13. The controlled-release composition of embodiment P11 orP12, wherein the composition comprises 0.2 to 6 mg of analpha-adrenergic agent per dose.

Embodiment P14. The controlled-release composition of embodiment P13,wherein the composition comprises 0.5 to 4 mg of an alpha-adrenergicagent per dose.

Embodiment P15. The controlled-release composition of embodiment P14,wherein the composition comprises from 0.5 to 3 mg of analpha-adrenergic agent per dose.

Embodiment P16. The controlled-release composition of any one ofembodiments P1 to P15, wherein the alpha-adrenergic agent is selectedfrom naturally occurring or synthetic alpha-adrenergic agents.

Embodiment P17. The controlled-release composition of any one ofembodiments P1 to P16, wherein the alpha-adrenergic agent is selectedfrom an alpha-1 agonist and an alpha-2 agonist.

Embodiment P18. The controlled-release composition of any one ofembodiments P1 to P17, wherein the alpha-adrenergic agent is selectedfrom amidephrine, anisodamine, anisodine, chloroethylclonidine,cirazoline, desvenlafaxine, dipivefrine, dopamine, ephedrine,epinephrine (adrenaline), etilefrine, ethylnorepinephrine,5-fluronorepinephrine, 6-fluoronorepinephrine, indanidine,levonordefrin, metaraminol, methoxamine, methyldopa, midodrine,naphazoline, norepinephrine (noradrenaline), octopamine, oxymetazoline,phenylephrine, phenylpropanolamine, pseudoephedrine, synephrine,tetrahydrozoline, xylometazoline,6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole,A-61603(N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide)and salts of any one thereof.

Embodiment P19. The controlled-release composition of embodiment P18,wherein the alpha-adrenergic agent is oxymetazoline or a salt thereof.

Embodiment P20. A method for treating ptosis in a subject, comprisinginjecting a therapeutically effective amount of an alpha-adrenergicagent into the eyelid of the subject.

Embodiment P21. A method for cosmetic therapy of a subject, comprisinginjecting a therapeutically effective amount of an alpha-adrenergicagent into the eyelid of the subject.

Embodiment 22. The method of embodiment P20 or P21, wherein theinjection is administered intradermally, subcutaneously, pre-septally,post-septally, into the post-septal fat pad, or intramuscularly.

Embodiment P23. The method of embodiment P22, wherein thealpha-adrenergic agent is administered intramuscularly.

Embodiment P24. The method of embodiment P23, wherein the intramuscularinjection is administered into Müller's muscle or the levator muscle orboth.

Embodiment P25. The method of embodiment P21, wherein the injection isadministered adjacent to Müller's muscle or the levator muscle or both.

Embodiment P26. The method of any one of embodiments P20 to P25, whereinthe alpha-adrenergic agent is formulated as the controlled-releasecomposition of any one of embodiments P1 to P10.

Embodiment P27. The method of any of embodiment P20 to P26, wherein thealpha-adrenergic agent is oxymetazoline or a salt thereof.

Embodiment P28. A method for treating ptosis in a subject, comprisingdirectly contacting Müller's muscle with an effective amount of analpha-adrenergic agent.

Embodiment P29. A method for cosmetic therapy of a subject, comprisingdirectly contacting Müller's muscle with an effective amount of analpha-adrenergic agent.

Embodiment P30. The method of embodiment P28 or P29, wherein the directcontact occurs through release of an alpha-adrenergic agent from animplant in the eyelid of the subject.

Embodiment P31. The method of embodiment P28 or P29, wherein the directcontact occurs through injection of the alpha-adrenergic agent intoMüller's muscle.

Embodiment P32. The method of any one of embodiments P28 to P31, whereinthe alpha-adrenergic agent is formulated as the controlled-releasecomposition of any one of embodiments P1 to P10.

Embodiment P33. The method of any one of embodiments P28 to P32, whereinthe alpha-adrenergic agent is oxymetazoline or a salt thereof.

Embodiment P34. A method for treating ptosis in a subject, comprisingadministering a controlled-release composition of an alpha-adrenergicagent to the eyelid of the subject wherein the controlled-releasecomposition releases an effective amount of an alpha-adrenergic agent tothe subject over a period of time.

Embodiment P35. A method for cosmetic therapy of a subject, comprisingadministering a controlled-release composition of an alpha-adrenergicagent to the eyelid of the subject wherein the controlled-releasecomposition releases an effective amount of an alpha-adrenergic agent tothe subject over a period of time.

Embodiment P36. The method of embodiment P34 or P35, wherein thecontrolled-release composition is selected from any one of embodimentsP1 to P19.

Embodiment P37. The method of embodiment P35, wherein thecontrolled-release composition is administered topically to the eyelid.

Embodiment P38. The method of embodiment P37, wherein thecontrolled-release composition releases an effective amount of analpha-adrenergic agent to the subject over a period of 6 hours or more.

Embodiment P39. The method of embodiment P35, wherein thecontrolled-release composition is administered by injection into theeyelid.

Embodiment P40. The method of embodiment P39, wherein thecontrolled-release composition is administered as an injectablepolymeric implant.

Embodiment P41. The method of embodiment P39 or P40, wherein thecontrolled-release composition releases an effective amount of analpha-adrenergic agent to the subject over a period of 2 weeks or more.

Embodiment P42. A method for increasing the vertical separation of theupper and lower eyelids of a subject, comprising administering aneffective amount of an alpha-adrenergic agent to the eye or eyelid of asubject.

Embodiment P43. The method of embodiment P42, wherein the subject doesnot have ptosis.

Embodiment P44. The method of embodiment P42 or P43, wherein thealpha-adrenergic agent is administered as a controlled-releasecomposition selected from any one of embodiments P1 to P14.

Embodiment P45. The method of embodiment P42 or P43, wherein thealpha-adrenergic agent is administered topically to the eye or eyelid.

Embodiment P46. The method of embodiment P45, wherein thealpha-adrenergic agent is administered to the eyelid of the subject.

Embodiment P47. The method of embodiment P42 or P43, wherein thealpha-adrenergic agent is injected into the eyelid of the subject.

Embodiment P48. The method of any one of embodiments P42 to P47, whereinthe vertical separation of the upper and lower eyelids is increased by10 percent or more relative to the pre-treatment separation of the upperand lower eyelids.

EXAMPLES Example 1. Evaluation of the Effect on the Eyelid RetractionAfter Administration of Oxymetazoline Solutions in Rabbits

Rabbits without ocular pathology received oxymetazoline solutions byocular injection. The evolution was tested postoperative, 1, 2, 3, 7,10, and 14 day after oxymetazoline solutions administration. Eyelidswere analyzed by histology at the end of the experiment. Endpointsincluded inflammation, fibrosis, pre- and post-septal fat, status oflevator muscle and Müller's muscle, presence of vascular injury ornecrosis or ischemic injury to eyelid tissues.

Material

-   -   Animals: female New Zealand rabbits (2.5-3 kg)    -   Sedation: atropine sulfate and midazolam IV (ear vein)    -   Anesthesia: induction with Propofol 1% (10 mg/kg) by ear vein    -   Maintenance with isoflurane (inhalant anesthesia)    -   Oxymetazoline solutions    -   Slit lamp

Method Baseline Measures (1st Phase)

-   I. Animals (n=2); 2.5-3 kg New Zealand rabbit-   II. Without sedation and anesthesia-   III. Photographic record with a ruler (to serve as a standard    measure of distance). Three sets of photos per measurements taken in    dim lighting to keep rabbits from squinting-   IV. 50 μl of 10% phenylephrine was administered via topical into the    right eye (RE)-   V. Photographic record with a ruler. Three sets of photos per    measurements. After 20-30 minutes post-dose.-   VI. Animals returned to animal housing.

Test Article (Oxymetazoline Solutions) (2nd Phase)

-   I. Animals (n=3/each group); 2.5-3 kg New Zealand rabbit-   II. Photographic record with a ruler (to serve as a standard measure    of distance). Three sets of photos per measurements taken in dim    lighting to keep rabbits from squinting.-   III. Sedation with atropine sulfate and midazolam-   IV. Induction with Propofol-   V. Maintenance with isoflurane-   VI. Ocular injection of oxymetazoline solutions or PBS    (phosphate-buffered saline)    -   a. Group A: oxymetazoline 1 mg/ml in PBS (RE) and PBS (LE)    -   b. Group B: oxymetazoline 3 mg/ml in PBS (RE) and PBS (LE)    -   c. Group C: oxymetazoline 10 mg/ml in PBS (RE) and PBS (LE)-   All animals were administered 100 μl (0.1 ml) of the oxymetazoline    solution (RE) or PBS vehicle control (LE) via an injection into the    post-septal fat pad, adjacent to Müller's muscle of both eyelids on    Day 0. For this injection, a 30 G needle was used; test article was    administered at least 4 mm away from the site of the needle entry to    prevent reflux of fluid through the hole.-   VII. Follow-up.-   VIII. Euthanized animals 14 days after the injection of    oxymetazoline solutions to process the eyelids tissues.-   a. Harvest both eyelids from each animal and store in formalin-   b. Histology (H/E staining)

Follow-Up

Follow-up included:

-   -   Eyelid retraction/ptosis measurements & digital photos with eyes        directly facing camera and a ruler in the frame of the        photograph to standardize distances. Three sets of photos per        measurement taken in dim lighting to keep rabbits from        squinting.    -   Slit-lamp biomicroscopy    -   Daily general health observations    -   Body weights prior to dosing and prior to sacrifice

Study Variables

-   I. Palpebral fissure distance-   II. Margin reflex distance 1

Results

-   Group A (1 mg/ml)-   Notes:-   pre-injection. Oxy injection performed without incidents;-   Day 2: pressure applied to close eyelid in Right Eye (3 h    post-injection). Animal show ocular discomfort-   Day 3 morning: pressure applied to close eyelid in Right Eye

#1 (Male. 2.8 Kg)/#2 (Male 3 Kg)/#3 (Male, 3 Kg) Right Left Eye (RE) Eye(LE) Day 2 Conjuctival +/+/+ +/+/+ Congestion Chemosis +/+/+ +/+/+Redness +/+/+ +/+/+ Threat Test Abolished/Abolished/ Delayed/+/Abolished Delayed Palpebral Reflex Abolished/Abolished/ +/+/+ AbolishedDay 3 Conjuctival +/+/+ −/−/− morning Congestion Chemosis +/+/+ −/−/−Redness +/+/+ +/+/+ Threat Test Abolished/Abolished/ +/+/+ AbolishedPalpebral Reflex Delayed/Delayed/ +/+/+ Delayed Day 3 Conjuctival +/+/+−/−/− afternoon Congestion Chemosis −/−/− −/−/− Redness −/−/− −/−/−Threat Test Delayed/Delayed/ +/+/+ Delayed Palpebral Reflex +/+/+ +/+/+Day 4 Conjuctival +/+/+ −/−/− morning Congestion Chemosis −/−/− −/−/−Redness −/−/− −/−/− Threat Test Delayed/Delayed/ +/+/+ Delayed PalpebralReflex +/+/+ +/+/+ Day 4 Conjuctival +/+/+ −/−/− afternoon CongestionChemosis −/−/− −/−/− Redness −/−/− −/−/− Threat Test Delayed/Delayed/+/+/+ Delayed Palpebral Reflex +/+/+ +/+/+ Day 5 Conjuctival −/−/− −/−/−Congestion Chemosis −/−/− −/−/− Redness −/−/− −/−/− Threat Test +/+/++/+/+ Palpebral Reflex +/+/+ +/+/+ Day 6 Conjuctival −/−/− −/−/−Congestion Chemosis −/−/− −/−/− Redness −/−/− −/−/− Threat Test +/+/++/+/+ Palpebral Reflex +/+/+ +/+/+ Day 7 Conjuctival −/−/− −/−/−Congestion Chemosis −/−/− −/−/− Redness −/−/− −/−/− Threat Test +/+/++/+/+ Palpebral Reflex +/+/+ +/+/+ Day 8 Conjuctival −/−/− −/−/−Congestion Chemosis −/−/− −/−/− Redness −/−/− −/−/− Threat Test +/+/++/+/+ Palpebral Reflex +/+/+ +/+/+Group B (3 mg/ml)Notes:pre-injection. Oxy injection performed without incidents;Day 2: pressure applied to close eyelid in Right Eye (3 hpost-injection). Animal show ocular discomfortDay 3 morning: pressure applied to close eyelid in Right EyeDay 3 afternoon: pressure applied to close eyelid in Right EyeDay 4 morning: pressure applied to close eyelid in Right Eye

#1 (Male. 3 Kg)/#2 (Male 2.9 Kg) Right Left Eye (RE) Eye (LE) Day 2Conjuctival +/+ +/+ Congestion Chemosis +/+ +/+ Redness +/+ +/+ ThreatTest Abolished/Abolished Delayed/+/ Delayed Palpebral ReflexAbolished/Abolished +/+ Day 3 Conjuctival +/+ −/− morning CongestionChemosis +/+ −/− Redness +/+ +/+ Threat Test Abolished/Abolished +/+Palpebral Delayed/Delayed +/+ Reflex Day 3 Conjuctival +/+ −/− afternoonCongestion Chemosis −/+ −/− Redness −/− −/− Threat TestAbolished/Abolished +/+ Palpebral Reflex Delayed/Delayed +/+ Day 4Conjuctival +/+ −/− morning Congestion Chemosis −/− −/− Redness −/− −/−Threat Test Delayed/Delayed +/+ Palpebral Reflex Delayed/Delayed +/+ Day4 Conjuctival +/+ −/− afternoon Congestion Chemosis −/− −/− Redness −/−−/− Threat Test Delayed/Delayed +/+ Palpebral Reflex +/+ +/+ Day 5Conjuctival −/− −/− Congestion Chemosis −/− −/− Redness −/− −/− ThreatTest Delayed/ +/+ Palpebral Reflex +/+ +/+ Day 6 Conjuctival −/− −/−Congestion Chemosis −/− −/− Redness −/− −/− Threat Test +/+ +/+Palpebral Reflex +/+ +/+ Day 7 Conjuctival −/− −/− Congestion Chemosis−/− −/− Redness −/− −/− Threat Test +/+ +/+ Palpebral Reflex +/+ +/+ Day8 Conjuctival −/− −/− Congestion Chemosis −/− −/− Redness −/− −/− ThreatTest +/+ +/+ Palpebral Reflex +/+ +/+

Example 2. Diagnostic Method

A single drop of phenylephrine 2.5% or 10% is administered to the eye ofa subject with ptosis or a subject who would like to elevate the uppereyelid for cosmetic purposes or otherwise. The treated eye is observedto see how the eyelid responds to the administration. The response ofthe eyelid to the phenylephrine can be used to determine whether thepatient will be responsive to treatment with an alpha-adrenergic agentfor treating ptosis or elevating the upper eyelid for cosmetic or otherpurposes. The dosage, frequency and methods of administration of thealpha-adrenergic agent for treating ptosis or elevating the upper eyelidfor cosmetic or other purposes can also be determined.

Example 3. Treatment of Ptosis

A sustained-release composition of oxymetazoline, e.g., from about 0.5mg to about 4 mg, is injected into one eyelid, for unilateral ptosis, orboth eyelids, for bilaterial ptosis, of a subject suffering from ptosis.The subject receives the injection as part of a treatment regimen thatincludes biweekly, monthly or bimonthly injections of oxymetazoline. Thesubject may also apply a topical pharmaceutical composition ofoxymetazoline, e.g., 0.5 mg to 2 mg per dose, on an as needed basis.

Example 4: Cosmetic Treatment by Injection

A sustained-release composition of oxymetazoline, e.g., from about 0.5mg to about 4 mg, is injected into the eyelid of a subject for cosmeticpurposes. The subject receives the injection as part of a treatmentregimen that includes biweekly, monthly or bimonthly injections ofoxymetazoline. The subject may also apply a topical pharmaceuticalcomposition of oxymetazoline on an as needed basis.

Example 4: Cosmetic Treatment by Topical Application to the ExteriorSurface of the Eyelid

A dermatological composition of oxymetazoline, formulated foradministration to the exterior surface of the upper eyelid, is appliedto the eyelid of a subject in need thereof. The composition may beformulated as a lotion, a cream or make-up such as eyeshadow oreyeliner. The subject applies the composition as needed, such as once ortwice daily.

We claim:
 1. A cosmetic gel composition for the eyelid comprising analpha-adrenergic agent and a permeation enhancer, wherein a dose of thecosmetic gel composition comprises from about 0.5 mg to 8 mg of thealpha-adrenergic agent wherein the alpha-adrenergic agent isoxymetazoline or a salt thereof, wherein the permeation enhancer is lessthan 40% by weight of the total composition, and wherein the cosmeticgel composition comprises one or more cosmetic excipients.
 2. Thecosmetic gel composition of claim 1, wherein the dose of the cosmeticgel composition comprises from about 3 to 6 mg of oxymetazoline or asalt thereof.
 3. The cosmetic gel composition of claim 1, wherein thepermeation enhancer is less than 30% by weight of the total composition.4. The cosmetic gel composition of claim 1, wherein the permeationenhancer is less than 20% by weight of the total composition.
 5. Thecosmetic gel composition of claim 1, wherein the permeation enhancer isselected from ethanol, propylene glycol,dodecyl-N,N-dimethyl-aminoacetate, ethylacetate, azone, sodium dodecylsulfate, d-limonene, oleic acid, 1,3-diphenyl-urea,N-methyl-2-pyrrolidone, beta-cyclodextrin, and dimethylsulfoxide.
 6. Thecosmetic gel composition of claim 1, wherein said permeation enhancercomprises an alcohol.
 7. The cosmetic gel composition of claim 6,wherein said permeation enhancer comprises propylene glycol.
 8. Thecosmetic gel composition of claim 1, wherein said cosmetic gelcomposition is a controlled-release composition.
 9. The cosmetic gelcomposition of claim 5, wherein the permeation enhancer increases skinpermeation of the alpha-adrenergic agent or the salt thereof by about0.5 mm or more relative to a composition without the permeationenhancer.
 10. The cosmetic gel composition of claim 5, wherein thepermeation enhancer increases skin permeation of the alpha-adrenergicagent or the salt thereof by about 2-fold or greater relative to acomposition without the permeation enhancer.
 11. The cosmetic gelcomposition of claim 10, wherein the permeation enhancer increases skinpermeation of oxymetazoline or a salt thereof by about 3-fold or greaterrelative to a composition without the permeation enhancer.
 12. Thecosmetic gel composition of claim 1, further comprising one or moredermatologically acceptable carriers.
 13. The cosmetic gel compositionof claim 1, wherein the one or more dermatologically acceptable carriersare individually selected from buffers, preservatives, gelling agents,rheological modifiers and stabilizers, moisturizers, and humectants. 14.The cosmetic gel composition of claim 1, wherein the one or morecosmetic excipients are individually selected from sunscreens,fragrances, pigments and antioxidants.
 15. A method of contactingMuller's muscle with an alpha-adrenergic agent, comprising applying adose of the cosmetic gel of claim 1 to the exterior surface of the uppereyelid of a subject.
 16. A method of permeating the septal fat pad withan alpha-adrenergic agent, comprising applying a dose of the cosmeticgel of claim 1 to the exterior surface of the upper eyelid of a subject.